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CAS No. : | 79-33-4 | MDL No. : | MFCD00064266 |
Formula : | C3H6O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 90.08 | Pubchem ID : | - |
Synonyms : |
(S)-2-Hydroxypropanoic acid
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 19.47 |
TPSA : | 57.53 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.36 cm/s |
Log Po/w (iLOGP) : | -0.02 |
Log Po/w (XLOGP3) : | -0.72 |
Log Po/w (WLOGP) : | -0.55 |
Log Po/w (MLOGP) : | -0.85 |
Log Po/w (SILICOS-IT) : | -0.8 |
Consensus Log Po/w : | -0.59 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | 0.12 |
Solubility : | 119.0 mg/ml ; 1.32 mol/l |
Class : | Highly soluble |
Log S (Ali) : | -0.01 |
Solubility : | 87.6 mg/ml ; 0.972 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.98 |
Solubility : | 866.0 mg/ml ; 9.62 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.29 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With marine microbial esterase In aq. phosphate buffer at 37℃; for 1 h; Resolution of racemate; Enzymatic reaction | A standard 500‐μL hydrolytic reaction system containing140 μg purified esterase PHE14, 50 mmol/L substrate (racemicmethyl lactate) and 50 mmol/L phosphate buffer (pH 7.5) wasincubated at 37 °C for 1 h. After the completion of the enzymaticreaction, reaction samples were extracted with an equalvolume of ethyl acetate and the organic phase was further analyzedto evaluate the enzymatic resolution of (±)‐methyl lactate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84 % ee | With marine microbial esterase In aq. phosphate buffer at 37℃; for 1 h; Resolution of racemate; Enzymatic reaction | A standard 500‐μL hydrolytic reaction system containing140 μg purified esterase PHE14, 50 mmol/L substrate (racemicmethyl lactate) and 50 mmol/L phosphate buffer (pH 7.5) wasincubated at 37 °C for 1 h. After the completion of the enzymaticreaction, reaction samples were extracted with an equalvolume of ethyl acetate and the organic phase was further analyzedto evaluate the enzymatic resolution of (±)‐methyl lactate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In toluene | |
With copper(II) sulfate | ||
With sulfuric acid; benzene durch azeotrope Destillation; |
With sulfuric acid at 78℃; for 10h; | 2.5 Step 5: Esterification reaction was conducted for 10 hrs after heating filtrate from step 3 at 78° C. After the reaction, the filtrate was analyzed by gas chromatography. The amount of ethyl lactate produced was 15 g. | |
With N,N,N-triethyl-N-(propanesulfonic acid)ammonium hydrogensulfate In cyclohexane at 85℃; for 10h; | 8 Example- 8 Weighing 0.5g c sulfonic acid triethylamine bisulphate ionic liquid and 9.01g lactic acid and 9.21g in ethanol into the reaction bottle, then adding 20 ml of cyclohexane with water as, stirring, the control temperature is 85 °C, the reaction time is 10 hours, reaction standstill, gravity sedimentation, the esterification product of lactic acid ethyl ester from the liquid, and then out the spin vaporization of decompress cyclonexane and ethanol. The esterification rate 98%, selectivity of 100%, the lower the ionic liquid can be recycled after the arefaction. | |
With Purolite C100 MBH In water for 6h; Reflux; | Esterification of lactic acid. Concentration of 250 g of a 79% aqueous solution of lactic acid for 1 h at 90°C under reduced pressure on an IKA RV 10 basic rotary evaporator afforded 100% lactic acid after removal of 52.5 g of water. A mixture of 50 g (0.56 mol) of 100% lactic acid, 129 g of 80% aqueous ethanol, and 7.5 g of Purolite C100 MBH (5 wt % of the overall amount of lactic acid and ethanol) was refluxed for 6 h with continuous stirring. The mixture was cooled to room temperature, the catalyst was filtered off, and the mixture was distilled under atmospheric pressure to collect a fraction boiling in the range from 78 to 150 °C. | |
With sulfuric acid In benzene at 65℃; for 4h; | 2 Example 2 In the preparation method of (R)-(+)-2-p-hydroxyphenoxypropionic acid of the present invention, (S)-(-)-lactic acid 45.5 g (0.5 mol) is added to a 500 mL four-necked flask. , 100mL benzene, stirring. Heat the reaction solution to 65 ° C, start adding 100mLA mixture of absolute ethanol and 2 mL of concentrated sulfuric acid was added dropwise over 1 h, and then the reaction was kept for 3 h. The reaction was completed, and (S)-(-)-ethyl lactate was obtained under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With tert.-butylnitrite; In 1,4-dioxane; water; at 20℃; for 1h;Inert atmosphere; | General procedure: The Boc-protected amino acid (1 mmol) was treated with TFA (3 mL) for 15 minutes. Afterevaporation the residue was dissolved in dioxane-water (1:1, 4 mL) and the flask wasplaced in an ice bath. tert-Butylnitrite (0.13 mL, 1.1 mmol) was added and stirring wasmaintained under nitrogen at room temperature for one hour. After pouring the reactionmixture onto celite and evaporation (50 Pa, 30 C) into a dry free-floating powder,separation was performed utilizing a CombiFlash Rf (Teledyne ISCO) automated flashchromatography apparatus by means of AcOH-MeOH-EtOAc (1:9:90) on a normal phasesilica column affording the pure a-hydroxy carboxylic acid in the yield specified in Table 1.HO-His(Bom)-OH and HO-Arg(Tos)-OH were isolated by adding water (30 mL) to thereaction mixture followed by freeze drying and HPLC purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.2% | In tetrahydrofuran; at -10 - 20℃; for 5h; | Take L-lactic acid 12.0g (133.3mmol) in250ml three reaction flask,Add 24ml of anhydrous tetrahydrofuran,After 19.2 ml (266.6 mmol) of acetyl chloride was added dropwise with stirring at -10 to 0 C, the mixture was stirred at room temperature for 5 hours,Concentration under reduced pressure at 35 C gave 14.6 g of a colorless oily liquid, yield 83.2%. |
6 g | With acetic acid; In dichloromethane; at 20℃; for 16h;Cooling with ice; | Preparation of (S)-tert-Butyl 2-hydroxypropanoate A solution of (S)-2-hydroxypropanoic acid (5.0 g, 55 mmol) and acetic acid (1 mL) in dichloromethane (40 mL) was cooled in an ice bath and treated dropwise with acetyl chloride (4.5 mL, 61 mmol). After addition was complete, the mixture was stirred at ambient temperature for 16 h. After this time, the mixture was diluted with water (50 mL) and extracted with methylene chloride (2*50 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-acetoxypropanoic acid (6.0 g) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; In water; for 1.66667h;Heating / reflux; | Example 18 Preparation of Compound (33) Compound (33) was prepared according to the method of Scheme 3. 1,2-diaminobenzene (10.81 g, 0.1 mol) and (2S)-2-hydroxypropanoic acid (15.90 g, 85+% in water from Aldrich, 0.15 mol) were mixed in 100 ml of 6 N HCl and refluxed for 100 minutes. Cooled down in ice bath, the reaction mixture was neutralized with aqueous NH3 solution. The precipitate was collected by filtration, washed with water, and then vacuum dried. The intermediate (1S)-1-(1H-benzimidazol-2-yl)ethanol (14.52 g) was obtained in 90% yield. |
80% | In neat (no solvent); at 140℃;Green chemistry; | General procedure: A mixture of organic acid (40 mmol) and o-phenylenediamine(40 mmol), thoroughly grounded with a pestle in a mortar at roomtemperature until liquefied, was subsequently heated at 140 C for1.5e2 h. The progress of the reaction was monitored by thin-layerchromatography (TLC). After cooling, the resulting mass waswashed with water, filtered, and the final product was recrystallized.The synthesized 2-benzimidazoles were then characterizedand confirmed by comparing their physical data with thoseof literature known compounds, as follows.2.2.1. Synthesis 2-substituted benzimidazoles2.2.1.1. (1A) (S)-1-(1H-Benzo[d]imidazole-2-yl)ethanol, colourlesssolid. Yield 80%; m.p.177-178 C, similar to [26] (m.p.176-178 C) IR(cm1, KBr): 3356 (aromatic eNH bending), 3364 (OH stretching),3070 (aromatic CeH stretching), 1505 (CeN stretching), 1458 (-C]C stretching),1315 (-C-N stretching); 1H-RMN: d 7,58 (d, 2H), 7,26 (t,2H),1,72 (d, 3H, CH3), 5,21 (q, 1H), 2.3 (brs, 1H, NH), 2,28 (s, 1H, OH).Elemental analysis (%) found for C9H10N2O: C, 66.57; H, 6.25; N,17.29; O, 9.89. calcd.: C, 66.65; H, 6.21; N, 17.27; O, 9.86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(i), (ii) /BRN= 385737/; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride | ||
With sulfuric acid In benzene at 65℃; for 4h; | 5 Example 5 In the preparation method of (R)-(+)-2-p-hydroxyphenoxypropionic acid of the present invention, (S)-(-)-lactic acid 45.5 g (0.5 mol) is added to a 500 mL four-necked flask. , 100mL benzene, stirring. Heat the reaction solution to 65 ° C, start dropping 120mLA mixture of anhydrous benzyl alcohol and 2 mL of concentrated sulfuric acid was added dropwise in 1 hour, and then the reaction was kept for 3 hours. The reaction was completed, and (S)-(-)-benzyl lactate was obtained under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid | ||
With sulfuric acid In toluene at 120℃; for 16h; Dean-Stark; | 8.1 Steo 1: Nonyl (S)-2-hydroxypropanoate A mixture of nonan-1-ol(18.01 g, 111 mmol), (S)-2-hydroxypropanoic acid (5 g, 55.5 mmol) and sulfuric add (1ml, 55.5 mmol) in toluene (50 mL) was heated at 120 °C for 16 hours and the water generated was removed with Dean-Stark condensor. The reaction was evaporated to dryness and the residue was diluted with EtOAc (100 L). The resulting solution was washed with water (30 mL).aqueous NaHCOs (30 L), brine (30 mL), dried over anhydrous sodium sulfate and concentrated to dryness under vaccum. The crude product was purified by flash column chromatography (silica gel, 330 g, pet. ether: EtOAc = 2:1) to give the title compound (9 g, 80%, yleld: 80%) as colorless oil. LCM8 (ESI) m/z calcd for C12H24O3: 218; found: 217 (M+1). 1H NMR (300 MHz, Chloroform-d) d 4.28 (q, J = 8.9 Hz, 1 H), 4.23 -4.11 (m, 2H), 1.67 - 1.84 (m, 2H), 1.41 (d, J = 6.9 Hz, 3H), 1.34 - 1.24 (m, 12H), 0.89 - 0.86 (m, 3H). | |
With sulfuric acid In toluene at 120℃; for 16h; Dean-Stark; | 8.1 Steo 1: Nonyl (S)-2-hydroxypropanoate A mixture of nonan-1-ol(18.01 g, 111 mmol), (S)-2-hydroxypropanoic acid (5 g, 55.5 mmol) and sulfuric add (1ml, 55.5 mmol) in toluene (50 mL) was heated at 120 °C for 16 hours and the water generated was removed with Dean-Stark condensor. The reaction was evaporated to dryness and the residue was diluted with EtOAc (100 L). The resulting solution was washed with water (30 mL).aqueous NaHCOs (30 L), brine (30 mL), dried over anhydrous sodium sulfate and concentrated to dryness under vaccum. The crude product was purified by flash column chromatography (silica gel, 330 g, pet. ether: EtOAc = 2:1) to give the title compound (9 g, 80%, yleld: 80%) as colorless oil. LCM8 (ESI) m/z calcd for C12H24O3: 218; found: 217 (M+1). 1H NMR (300 MHz, Chloroform-d) d 4.28 (q, J = 8.9 Hz, 1 H), 4.23 -4.11 (m, 2H), 1.67 - 1.84 (m, 2H), 1.41 (d, J = 6.9 Hz, 3H), 1.34 - 1.24 (m, 12H), 0.89 - 0.86 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.6% | With lithium aluminium tetrahydride In tetrahydrofuran | |
With lithium aluminium tetrahydride | ||
> 99 % ee | With sulfuric acid; hydrogen In water at 80℃; for 5h; |
With sulfuric acid; hydrogen In water at 80℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | A solution of L-(+)-lactic acid 4 (5.0 g, 55.5 mmol) in DMF (200 mL) was heated to 100 C, treated with KOH (3.74 g, 66.6 mmol), and stirred for 1 h. Benzyl bromide (7.6 mL, 63.8 mmol) was added and the mixture was stirred and heated at 100 C for another 16 h. After cooling to r.t., the solvent was evaporated under reduced pressure. The residue was taken up in CH2Cl2 (200 mL), washed with H2O (200 mL), and the aqueous phase was extracted with CH2Cl2 (200 mL). The combined organic phases were dried over MgSO4 and the crude product was purified by column chromatography (silica gel 60; hex-anes/EtOAc, 4:1) to give (S)-5. Yield: 6.94 g (78%); colourless oil; Rf = 0.59 (hexanes/EtOAc, 2:1); [alpha]D25 -14.4 (c 4.0, MeOH) [Lit.28 -15.9 (c 4.0, MeOH)]. IR (ATR): 3424, 1731, 1198, 1122, 1043, 735, 696 cm-1. 1H NMR (300 MHz, CDCl3): delta = 1.34 (d, J = 6.9 Hz, 3 H, CH3), 3.45 (s, 1 H, OH), 4.19-4.30 (m, 1 H, CH), 5.10 (s, 2 H, OCH2), 7.21-7.29 (m, 5 H, Ar-CH). 13C NMR (75.5 MHz, CDCl3): delta = 20.0 (C3), 66.6 (C2), 66.7 (OCH2), 127.9, 128.1, 128.3 (Ar-CH), 135.1 (Ar-Cq), 175.1 (C1). MS (EI, 70 eV): m/z (%) = 180 (3) [M+], 108 (4), 91 (100), 89 (3), 77 (6), 65 (12), 51 (2), 46 (3). | |
76% | 1,8-Diazabicyclo[5.4.0]undec-7-ene (18 mL, 18.3 g, 0.12 mole) was added slowly, with stirring, to a solution of 85% (S)-lactic acid (12.7 g, 0.12 mole) in methanol (50 mL). The solvent was removed under reduced pressure at 70-80 C., and the resulting oil, in dimethylformamide (50 mL), was cooled to 15 C. Benzyl bromide (11.9 mL, 17.1 g, 0.10 mole) was added dropwise and the reaction mixture was stirred at room temperature for 30 h. After removal of approximately 40 mL of solvent by vacuum distillation, ethyl acetate (100 mL) was added, followed by water (30 mL). The aqueous layer was washed with ethyl acetate (2×30 mL) and the combined organic extracts were washed successively with water (30 mL), 5% citric acid (30 mL), water (30 mL), saturated sodium bicarbonate (3×30 mL) and saturated sodium chloride (2×30 mL), dried over anhydrous magnesium sulfate, and evaporated. The crude product was distilled, to give a colourless oil (13.8 g, 76%), b.p. 119-123/1 torr. 1Hmr (CDCl3, delta): 7.37 (5H, m, Ar), 5.21 (2H, s, PhCH2), 4.32 (1H, q, 6.9 Hz, CH), 2.38 (1H, br s, OH), 1.43 (3H, d, 6.9 Hz, CH3).). 13Cmr (CDCl3, delta): 175.52, 135.23, 128.66, 128.54, 128.22, 67.31, 66.84, 20.37. IR (neat): 3483, 1738 cm-1. Mass spectrum (CI, m/z): 181 (M+1).). Calcd. for C10H12O3: C, 66.64; H, 6.73. Found: C, 66.30; H, 6.75. | |
73% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | Benzyl bromide (56.4?mg, 0.33?mmol) and Cs2CO3 (107?mg, 0.33?mmol) were added to a solution of l-lactic acid (27?mg, 0.3?mmol) in dimethylformamide (1?ml). The reaction mixture was stirred for 4?h at room temperature. After the addition of ethyl acetate, the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The organic phase was concentrated in vacuo. The resulting residue was fractionated by silica gel column chromatography to yield benzyl lactate (39.3?mg, 73% yield). |
70% | With caesium carbonate; In acetonitrile; for 48h;Reflux; | Benzyl bromide (242 g, 1.42 mol) was added to a suspension of (2S)-2-hydroxy propanoic acid (106 g, 1.18 mol) and cesium carbonate (503 g, 1.53 mol) in acetonitrile (1 L) at room temperature, and the resulting mixture was heated under reflux for 2 days. After cooling to room temperature, the mixture was quenched with water (2 L), extracted with EtOAc (3 x 800 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexane: EtOAc= 10: 1 to 5: 1) to give the title compound (150 g, 70%). 1H NMR (400 MHz, CDC13): delta 7.38 (m, 5H), 5.22 (s, 2H), 4.33 (q, 1H), 1.44 (d, 3H). |
61% | To a well stirred solution of L-lactic acid (1g, 11.1 mmol) in dry DMF (20 mL), K2CO3 (0.534 g, 22.2 mmol) was added under nitrogen atmosphere at 0 C. After 10-15 mins, benzyl bromide (1.4 mL, 12.2 mmol) was added and the reaction was allowed to proceed for 1 h at rt. The reaction mixture was then poured into the ice-water (30 mL) and extracted with ethyl acetate. Organic fraction was dried over anhydrous sodium sulphate and subjected to column chromatography to separate excess benzyl bromide. This compound was obtained as colourless liquid; yield = (1.2 g/ 1.0 g of L-lactic acid; 61%) | |
44.4% | 1 mol of compound 4 was dissolved in 1 L of methanol, and 1 mol of a 1 mol/L aqueous solution of Cs2CO3 was added dropwise thereto at 0C.The reaction was maintained at 0C for 30 minutes and then allowed to warm to room temperature for 2 hours. After vacuuming to remove methanol and water,The reaction was vacuum dried overnight. The residue was dissolved in 1 L of N,N-dimethylformamide (DMF).1.2 mol of benzyl bromide (BnBr) was added and reacted at room temperature for 20 hours. Remove DMF in vacuumThe residue was extracted three times with 400 mL each of ethyl acetate. The combined organic phases were washed with 400 mL of brine, dried over Na2SO4, filtered and concentrated.The residue was purified on a silica gel column using a petroleum ether/ethyl acetate (5/1) gradient to a colorless oil, yielding 80 g,Compound 4-1, yield 44.4% | |
41% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 96h; | <strong>[79-33-4]L-Lactic acid</strong> (467g, 5.2mol, anhydrous) was dissolved in DMF (1 L). Cesium carbonate (847g, 2.6mol, 0.5eq) was added with stirring, followed by benzyl bromide (886g, 5.18mol, 0.99eq) over about 45 minutes. The mixture was stirred at room temperature for 4 days, after which time analysis showed the reaction to be complete. Heteroneous mixture was filtered through Celite; the filter cake was washed with ethyl acetate (2 x 500ml_). The filtrate was extracted with water (2 x 500ml_), saturated aqueous Na2C03 (4 x 500ml_) and brine (2 x 500ml_), then concentrated in vacuo to yield a thick orange oil, 775g, 80%. This was purified by dry flash chromatography using EtOAc/heptane (0% to 10%) as eluent. Appropriate fractions were combined and concentrated in vacuo to yield benzyl-L-lactate, 385g, 41 %. 1H NMR (CDCIs, 300 MHz): d 7.40-7.35 (m, 5H), 5.21 (s, 2 H), 4.37-4.27 (m, (0293) 1 H), 2.79 (d, 1 H), 1.43 (d, 3H). |
41% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 96.75h; | <strong>[79-33-4]L-Lactic acid</strong> (467g, 5.2mol, anhydrous) was dissolved in DMF (1 L). Cesium carbonate (847g, 2.6mol, 0.5eq) was added with stirring, followed by benzyl bromide (886g, 5.18mol, 0.99eq) over about 45 minutes. The mixture was stirred at room temperature for 4 days, after which time analysis showed the reaction to be complete. Heteroneous mixture was filtered through Celite; the filter cake was washed with ethyl acetate (2 x 500m L). The filtrate was extracted with water (2 x 500m L), saturated aqueous Na2C03 (4 x 500m L) and brine (2 x 500m L), then concentrated in vacuo to yield a thick orange oil, M2, 775g, 80%. This was purified by dry flash chromatography using EtOAc/heptane (0% to 10%) as eluent.Appropriate fractions were combined and concentrated in vacuo to yield benzyl-L- lactate, 385g, 41 %.1H NMR (CDCl3 , 300 MHz): d 7.40-7.35 (m, 5H), 5.21 (s, 2 H), 4.37-4.27 (m, 1 H), 2.79 (d, 1 H), 1.43 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In ethyl acetate; at 0 - 20℃; for 12.33h; | (+) lactic acid (85%, 9.6 g, 90 mmol) was dissolved in ethyl acetate (400 mL) and a solution of Compound XLIX (19 g, 100 mmol) dissolved in ethyl acetate (200 mL) was added at 0 C. over 20 minutes. The resulting solution was stirred for 12 hours at room temperature. The resultant was concentrated under reduced pressure and applied to column chromatography (SiO2, EA:n-hex=1:6) to yield Compound L (17 g (76%)).[alpha]D=-9.41 (C=5.00, CHCl3)1H NMR (600 MHz, chloroform-d1) delta=7.357.24 (m, 10H), 6.92 (s, 1H), 4.39 (m, 1H), 2.76 (d, J=5.4 Hz, 1H), 1.47 (d, J=7.2 Hz, 3H) |
76% | In ethyl acetate; at 0℃; for 0.333333h; | (+) lactic acid (85%, 9.6 g, 90 mmol) was dissolved in ethyl acetate (400 mL) and a solution of Compound XLIX (19 g, 100 mmol) dissolved in ethyl acetate (200 mL) was added at 0 over 20 minutes. The resulting solution was stirred for 12 hours at room temperature. The resultant was concentrated under reduced pressure and applied to column chromatography (SiO2, EA : n-hex =1 : 6) to yield Compound L (17 g (76%)). [alpha]D = - 9.41 (C = 5.00, CHCl3) 1H NMR (600MHz, chloroform-d1) delta = 7.35?7.24(m, 10H), 6.92(s, 1H), 4.39(m, 1H), 2.76(d, J = 5.4Hz, 1H), 1.47(d, J = 7.2Hz, 3H) |
43% | In acetonitrile; at 0 - 4℃; | A solution of Compound 35a (10.60 g, 100 mmol) in acetonitrile (72 mL) was cooled to 0C. A solution of diphenyldiazomethane (6.99 g, 36 mmol) in acetonitrile (18 mL) was then added drop-wise thereto over 2 hours. The reaction solution stood at 4C overnight. After the insoluble was filtered, the reaction mixture was concentrated, and then diisopropyl ether was added to the residue. The resulting solid was filtered, and then dried under reduced pressure to yield Compound 35b as a white solid.Yield: 10.91 g, (43%)1H-NMR (CDCl3) delta:1.48 (3H, d, J=6.9 Hz), 2.81 (1H, d, J=5.1 Hz), 4.34-4.42 (1H, m), 6.92 (1H, s), 7.24-7.38 (11H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In water; at 240℃; under 760.051 Torr;Inert atmosphere; Autoclave; | The catalytic reaction was carried out after loading 1 g of catalyst into a conventional stainless steel fixed bed reactor (inner diameter 5 mm, length 300 mm). Next, the 75%water-receiving LA was vaporized in the pre-heating line and mixed with N2 beforeintroduction into the reactor via the liquid pump. The product was recovered from thereactor through a heating line into a sample vessel maintained at 5 C, at which thecrude droplet and unreacted LA were separated into a crystalline phase and a liquid phase, respectively. |
79% | 90% hydrous lactic acid (9.02 g, 90.2 mmol)Docosanol (3.27 g, 10.0 mol),3-Cl-Py-T (0.254 g, 0.90 mmol) was placed in a 50 ml round bottom flask,In a distillation apparatus equipped with a vigreux tube, at 4 kPa at 140 C.,And heated for 12 hours. The mixture was heated and stirred at 140 C. and 25 mmHg (3333 Pa) for 12 hours.All of the flask residues are carboxylate esters of lactic acid oligomer,Its weight is 9.51 g (oligomer yield 95%),The degree of polymerization was Xn = 9.It was judged that all carboxylic acid ends were protected by being 1: 2.The obtained oligomer containing catalyst was heated at 160 C. and 1 mm Hg (133.3 Pa) for 3 hours,Depolymerization was carried out by heating and depressurization to obtain 5.09 g (79%) of lactide.The purity of this crude lactide, determined from 1 H-NMR,Chemical purity> 99.5 w / w%,Mesobody contamination rate 99.99% ee.The 90% by mass L-lactic acid aqueous solution used in this example was a low-The optical purity of L lactic acid is 99% ee. Or more.The optical purity of lactic acid was measured by a known HPLC method. | |
67.9% | With H-BEA; In toluene; for 3h;Dean-Stark; Heating; | In this example several zeolites were tested as catalyst for the synthesis of L-L-lactide from L-lactic acid. The following zeolites were used: CBV500, CBV600, CBV720, CBV760, and CBV780 (available from Zeolyst International, in NH4 or H-form); H-BEA (available from Sud- Chemie), NH4-ZSM-5 with various Si/AI2 ratios (available from Zeolyst International); H- MOR (available from Sud-Chemie); H-FER (available from Zeolyst International); H-MCM- 22 (available from ACSMaterial); LaX and LaY (made by starting from NaY or NaX, available from Evonik, according to C. F. Heylen and P. A. Jacobs, (Advances in Chemistry Series, 1973, 727, 490-500)). The zeolites were used in their Br0nsted acidic form (H-form). In general, when zeolites were provided (partly) exchanged with other cations (such as Sodium cations), they were exchanged and calcined to maximize the acidity and achieve the H-form. Typically, 100 mL of an aqueous solution of 0.5 M NH4CI was added per 1 .0 gram of (e.g. Na) zeolite on wet basis. The mixture was heated for 4 hours under reflux conditions. Then, the zeolite was isolated by filtration and the exchange procedure was repeated. The zeolite was isolated again, and washed with 1 L of water. In this way, the NH4-form of the zeolite is obtained. To transform this ammonium exchanged form into the Bransted acidic form, the zeolite was typically calcined for 12 hours at a temperature of 450C. A temperature ramp of 3C/min was applied. The resulting zeolites were stored at room temperature in contact with air. In a typical experiment, a reaction flask was loaded with a mixture of about 10 wt% L- lactic acid (L-LA) in toluene. Unless mentioned otherwise, the solution was prepared by mixing 1 g of 90 wt% L-LA (aqueous, obtained from Acros Organics) with 10 ml toluene. In one experiment (using the H-FER zeolite as catalyst), the solution was prepared by mixing 1 .65g of 50 wt% L-LA (aqueous, obtained from Sigma-Aldrich) with 10 ml toluene. In the conditions used for the experiments herein, no significant difference was observed between these starting solutions under these conditions. The zeolite was added to the reaction mixture (about 0.5 g of zeolite per 10 mL solution), and the mixture was heated by placing the reaction flask in a hot oil bath at a temperature of about 130C, and continuously mixed, the temperature of the reaction mixture was dependent on the used solvent and composition. A Dean-Stark trap was used for removal of water from the reaction mixture. Typically, the reaction mixture was heated for about 3 hours under stirring, after which the mixture was cooled to room temperature. The relative amounts of lactic acid oligomers, lactic acid, and lactide in the reaction mixture after 3 hours was indicative of the yield obtainable with each catalyst, as the reaction mixture typically does not change significantly after 3 hours for a good catalyst. This can be appreciated from Figure 1 , which shows the relative amount of reaction products in a reactor at different times, using a H-BEA zeolite catalyst with a Si/AI2 ratio of 25. However, it is noted that for some catalysts, the maximal concentrations may be obtained faster. Reference experiments were conducted using the known catalysts sulfuric acid (0.01 g per 10 mL solution) and Amberlyst 15 Wet (about 0.5 g per 10 mL solution). The amount of reference catalysts is chosen such that the total amount of acid sites is similar to the amount of acid sites of the zeolites, thus allowing a fair comparison. For each experiment, the total conversion rate of the lactic acid, and the lactide yield were determined via 1H NMR. Also control measurements using gas chromatography with flame ionization detector (GC/FID) and high-pressure liquid chromatography (HPLC) with uv-visible detector were performed. The total conversion of the lactic acid includes the fraction of lactic acid which had reacted to lactide, trimers, or other oligomers. The lactide yield only includes the fraction of fed lactic acid which has reacted to lactide. All zeolites having two or three interconnected and non-parallel channel systems, with at least one of said systems comprising 10-or more-membered ring channels and a framework Si/AI2 ratio of at least 24, and all zeolites having three interconnected and non- parallel channel systems, with at least two of said channel systems comprising 10-or more-membered ring channels and a framework Si/AI2 ratio of at least 6, provided lactide yields above 20%, up to about 70%. The results of the various experiments are summarized in Table 1. It is noted that for some zeolites, the framework Si/AI2 ratio, may differ from the bulk Si/AI2 ratio. For all zeolites, the framework Si/AI2 ratio is provided, as this is most relevant ratio for the catalysis. For some zeolites, the bulk Si/AI2 ratio is also provided (between brackets). Table 1 Number of Si/AI2 LA Lactide Catalyst interconnected Topology Ring size framework conversion yield Name non parallel rat... |
52.1% | Add 50ml of lactic acid to a 250ml three-necked bottle.Dehydration at elevated temperature (150 C)Under a vacuum of -0.10 MPa,Reaction 2h,Add 1 ml of catalyst,Gradually warmed up to 185 C,Reaction at a vacuum of 0.10 MPa for 15 hThe crude white lactide was distilled off under reduced pressure.The yield was 52.1%. | |
46% | Oligomerization oflactic acid in the presence of yttrium(III) and praseodymium(III) oxides and cerium(III) chloride, as well as in the absence of a catalyst, was carried out under continuous stirring under nitrogen (780 mm) in a flask maintained at a required temperature. The flask was connected with an air-cooled reflux condenser equipped with a bottom plate for removal of condensate. The reactions were carried out at 130, 150, and 180C for each catalyst. In each run, 0.569 g (2.52 mmol) of yttrium(III) oxide, 0.831 g (2.52 mmol) of praseodymium(III) oxide, or 1.885 g (5.06 mmol) of cerium(III) chloride heptahydrate was added to 36 g of a 79% aqueous solution of lactic acid. The mixture was heated for 4 h at a constant temperature. The condensate was removed from the plate receiver, and the still residue (lactic acid oligomers) was dissolved in DMSO-d6 and analyzed by 1H NMR. The degree of oligomerization (DPn) was determined from the ratio of the overall intensity of the CH proton signals of lactic acid and oligomers to the overall intensity of the CH proton signals of lactic acid and CHOH signals of oligomers according to [16]. Depolymerization and isolation of lactide. The mixture of lactic acid oligomers or oligoeesters and catalyst obtained after oligomerization was subjected to thermal decomposition. For this purpose, oligomer mixture, 3 g, was placed in a flask connected to an air cooled reflux condenser (receiver) and a trap cooled with liquid nitrogen. The flask was heated for 4 h at 180 or 200C at a residual pressure of 5 or 0.05 mm. The sublimate collected in the receiver was analyzed by 1H NMR. The yield was calculated as the weight ratio of lactide and initial oligomer. The concentration of lactide in the sublimate was determined by 1H NMR from the signal intensity ratio of lactide and naphthalene used as standard. The unsublimed residue (polylactide) was dissolved in tetrahydrofuran (3 mL), precipitated with methanol (100 mL) or diethyl ether (100 mL), and dried under reduced pressure. The molecular weight distribution of polylactide was determined by gel-permeation chromatography. | |
45.8% | A reactor was charged with 100 g of L-lactic acid (90% by mass content). Under an argon atmosphere at normal pressure, the reaction system was then heated to 150 and subjected to dehydration for 2 h. The pressure in the reactor was then reduced to 40 Torr, reacting at 150 C. for 4 h, to get the lactic acid oligomer (OLLA), with a weight average molecular weight of 1100 Da. (0020) The biogenic guanidine creatinine (CR) was added, to control the mass ratio of catalyst CR to L-lactic acid at 1:1000, and the reaction temperature at 200, vacuum degree of 10 torr, to react 3 h; then the distilled white crude L-lactide was collected. (0021) The collected crude L-lactide was washed with 8% alkali (sodium bicarbonate) solution, cleaned with the deionized water to neutral, vacuum dried 30 h at 35 C., to get white needle L-lactide, with the yield of 45.8% and specific rotation [alpha] 25 D=-277. | |
488 g | [0064] Polylactic acid oligomer was prepared from L(+)-lactic acid by following the experimental procedure given in Example 1. [0065] Preparation of Lactide [0066] A 1 L three-necked cylindrical glass reactor was equipped with a mechanical stirrer, a distillation condenser and a coiled receiver trap. The reactor was charged with 493 g of polylactic acid oligomer (number average molecular weight 1100) and 2.46 g (0.5 wt % based on oligomer) of tin powder (<150 mum) as a catalyst. The depolymerization was carried out at 160 C. for 1 h under nitrogen atmosphere; 180 C. for 1 h at 100 mm. Hg; 190 C. for 1 h at 10 mm. Hg and finally at 200 C. for 2 h at 0.01 mm. Hg. At the end of the above reaction period, 488 g (99% based on polylactic acid oligomer) of lactide was obtained. The lactide was further purified and characterized by HPLC using chiral columns. The chiral purity of purified lactide was 100% of L(+)-lactide. Yield: 99% | |
With SnO2(80)/SiO2; In water; at 240℃; under 760.051 Torr; for 100h;Inert atmosphere; | A fixed layer reactor is charged with 1 g of the SnO2(80)/SiO2 (20-40 mesh) catalyst produced in the above, maintained at 180 C. under a normal pressure, and provided with 75% L-aqueous solution of lactic acid (Aldrich) at a supply rate of 0.5 g/h simultaneously with nitrogen at a supply rate of 100 ml/min. (0061) Under the above condition, the (dehydration) reaction is continued for 100 hours. Gas chromatography analysis of the product showed that the conversion ratio of L-lactic acid is 88%, the selectivity of L-lactide is 98%, and the selectivity of meso-lactide is 2%, and oligomer of lactic acid are detected on the chromatogram. The above results are shown in Table 1 below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sulfuric acid; toluene-4-sulfonic acid; In pentane; at 45℃;Dean-Stark; Inert atmosphere; | To a solution of L-lactic acid (26 g, 290 mmol, 1 equiv) and pivaldehyde (25 g, 290 mmol, 1equiv) in pentane (290 mL) in a round-bottom flask equipped with a Dean-Stark apparatus underinert atmosphere and at 45 C was added PTSA (15 mg, 0.08 mmol,0.03 mol%) and conc. H2SO4 dropwise (30 drops). The reaction mixture was stirred at this temperature overnight and until enough water (expected 5.2 mL) collected in the Dean-Stark apparatus. The reaction mixture was cooled down to room temperature, diluted with Et2O and washed with saturated aqueous NaHCO3, water and brine, dried over Na2SO4, filtered though a pad of silica and carefully concentrated in vacuo to afford a volatile colourless oily syn/anti diastereomeric mixture. Three recrystallisations from pentane (1 mL/ 1 g of oil) under inert atmosphere and at -78 C provided acetal 54 as a colourless oil (23.5 g, 149 mmol, 52%, dr > 96:1 as determined by 1H NMR).1H NMR (400 MHz, CDCl3, 25 C): delta 5.13 (s, 1H, H-4), 4.34 (qd, J=6.7, 1.2 Hz, 1H, H-2), 1.47 (d, J=6.7 Hz, 3H, H-3), 0.97 (s, 9H, C(CH3)3) ppm. 13C NMR (100 MHz, CDCl3,25 C): delta 174.1 (C-1), 109.3 (C-4), 71.5 (C-2), 34.2 (C(CH3)3), 23.4 (C(CH3)3), 16.2(C-3) ppm. |
36% | With sulfuric acid; toluene-4-sulfonic acid; In tert-butyl alcohol; pentane; for 24h;Reflux; Dean-Stark; | General procedure: A solution of (R)-lactic acid (8.49 g, 95 mmol), pivalaldehyde (75% int-BuOH, 20.3 g, 177 mmol), p-toluenesulfonic acid monohydrate (0.005 g, 0.025 mmol) and conc. H2SO4 (0.25 mL) in pentane (85 mL)was heated to reflux with azeotropic removal of H2O under Dean-Stark conditions for 24 h. The mixture was then washed with H2O (2×100 mL), dried over MgSO4 and the solvent was removed under reduced pressure without heating to afford the crude product. Kugelrohr distillation (20 Torr) followed by recrystallisation frompentane at -78 C with collection of the crystalline product in acooled filtration funnel gave the product as colourless crystals, whichmelted to a colourless liquid below r.t. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With calcium hydroxide In water at 70 - 110℃; for 6h; | 2; 5 The same conditions described in Example 1 were used, with the exception of 6 moles of lactic acid are made to react with 4 moles of gluconic acid or the equivalent in glucono delta lactone. Also, 5 moles of calcium hydroxide or calcium carbonate in an aqueous medium, is used to obtain 3 moles of calcium lactate, 2 moles of calcium gluconate, and water.; The same conditions as described in Example 2 are used, with the exception of low pressure evaporation is used to achieve a concentration of approximately 50% to 80%, preferably 62%. Also, precipitating the mixture with methyl alcohol, ethyl alcohol or a mixture of the two in a V/V proportion of 3:1 to 6:1, preferably 5:1, and centrifuging mixture to separate the product obtained. |
Yield | Reaction Conditions | Operation in experiment |
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84% | With 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; | A solution of 0.47 g (1.69 mmol) (S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one in 15 ml tetrahydrofurane was treated at 0 C. with 0.17 g (1.86 mmol) L-lactic acid, 0.26 g (1.69 mmol) 1-hydroxybenzotriazole hydrate, 590 mul (3.38 mmol) N-ethyldiisopropylamine and 0.33 g (1.69 mmol) N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimid-hydrochlorid. After stirring at room temperature overnight the mixture was extracted with 1N aqueous hydrochloric acid/ethylacetate. Purification by chromatography on silicagel with ethylacetate/cyclohexane (0-100/100-0) yielded 0.50 g (84%) (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-hydroxy-propionamide as white solid; MS: m/e: 351.4 (M+H+), [alpha] 589=-131 (1% in MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; | c) (S)-N-((S)-1-Cyclopropylmethyl-5-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-hydroxy-propionamide Hydroxybenzotriazole (121 mg, 1 mmol), diisopropylethylamine (23 2 mg, 2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (172 mg, 1 mmol) were added to a cooled (0 C.) solution of (S)-3-amino-1-cyclopropyl-5-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one (220 mg, 1 mmol) and L-(+)-lactic acid (81 mg, 1 mmol) in THF (2 ml) and stirred overnight at r.t. The solvent was evaporated, the residue was taken up in dichloromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated. Upon chromatographic purification (silica gel, dichloromethane/methanol=1:0-9:1) the title compound (347 mg, quant.) was obtained as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetone at 17 - 35℃; for 10 - 24h; | 24 Example 24 Crystalline Carvedilol Lactate Preparation A suitable reactor is charged with acetone (50 mL). The acetone solution is sequentially charged with carvedilol (15.0 grams) and water (7 mL). Upon addition of the water, the slurry dissolves completely with heating To the solution is added 1 N aqueous D, L-Lactic acid (1 equiv. , 36.9 mL). The reaction mixture is stirred at between 17°C and 35 °C and seeded in one portion. The solid precipitate is formed over 10 hours to 24 hours. Later, the mixture is fi ltered and the cake is washed with a mixture of acetone and water (10 to 1) at 2 volume or 30 mL. The cake is dried under vacuum to a constant weight. The fin al weight is 9.16 grams. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 30 - 55℃; for 0.5h;Heated in sonicator; | In still some embodiments, decitabine salts were prepared from weak acids (3.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.7% | In ethyl acetate; isopropyl alcohol; at 15 - 25℃; for 2 - 24h;Product distribution / selectivity; | To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea (9.10 g, 24 mmol) in EtOAc-iPrOH (1 :1, 90 mL) was added L-lactic acid (2.25 g, 25 mmol). The mixture was stirred at ambient temperature for 24 h then reduced in vacuo. The residue was given consecutive slurries using toluene (100 mL) and Et2O (100 mL) and the resultant solid collected and dried (8.04 g).This solid was purified by recrystallisation from boiling iPrOH (200 mL) to give after drying l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-urea, L-lactate salt (5.7 g) as a beige solid.; l-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-rhoyrazol- 4-yl]-urea (1.859Kg, 4.872mol, l.Owt), propan-2-ol (9.00L5 5.0vol) and ethyl acetate (8.0OL, 4.5vol) were charged to a flange flask equipped with a mechanical stirrer and thermometer. The contents were stirred under nitrogen and L-lactic acid (0.504Kg, 5.59mol, 0.269wt) was added at 15 to 25C followed by a line rinse of ethyl acetate (0.90L, 0.5vol). The mixture was stirred at 15 to 25C for 120 to 140 minutes. The solid was isolated by filtration, the filter-cake washed with ethyl acetate (2x 2.00L, 2x l.Ovol) and pulled dry for 20 to 40 minutes. The filter-cake was dissolved in ethanol (33.00L, 17.7vol) at 75 to 850C, cooled to 65 to 700C and the solution clarified through glass microfibre paper. The filtrates were cooled to and aged at 15 to 250C for 2 to 3 hours. The crystallised solid was isolated by filtration, the filter-cake washed with ethanol (2x 1.00L, 2x 0.5vol) and pulled dry for at least 30 minutes. The solid was dried under vacuum at 35 to 45C to yield 1- cyclopropyl-3 - [3-(5 -morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4- yl]-urea l-lactic acid salt (1.386Kg, 58.7%th, 99.47% by HPLC area,) as a dark pink uniform solid.The infra-red spectrum of the lactate salt (KBr disc method) included characteristic peaks at 3229, 2972 and 1660 cm"1.Without wishing to be bound by any theory, it is believed that the infra red peaks can be assigned to structural components of the salt as follow:Peak: Due to:3229 cm"1 N-H2972 cm"1 aliphatic C-H1660 cm"1 urea C=O EPO <DP n="197"/> |
58.7% | In ethyl acetate; isopropyl alcohol; at 15 - 25℃; for 2 - 24h; | To a solution of 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H- pyrazol-4-yl]-urea (9.10 g, 24 mmol) in EtOAc-iPrOH (1 :1 , 90 mL) was added L-lactic acid (2.25 g, 25 mmol). The mixture was stirred at ambient temperature for 24 h then reduced in vacuo. The residue was given consecutive slurries using toluene (100 mL) and Et2O (100 mL) and the resultant solid collected and dried (8.04 g). <n="296"/>This solid was purified by recrystallisation from boiling iPrOH (200 mL) to give after drying 1 -cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-urea, ..-?lactate salt (5.7 g) as a beige solid.7-Morpholin-4-ylmethyl-2,4-dihydro-1 ,2,4,5a, 10-pentaaza-cyclopenta[a]fluoren-5-one (0.797Kg, 2.46mol, 1.0wt) and 1-methyl-2-pyrrolidinone (2.40L, 3.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.279Kg, 4.88mol, 0.351wt) was added at 15 to 300C under nitrogen. The contents were heated to 95 to 105C and stirred at this temperature for 16 to 24 hours. Reaction completion was determined by 1H NMR analysis. The reaction mixture was cooled to 10 to 200C and ethyl acetate (8.00L, 10.0vol) and sat. aq. sodium chloride (2.50L, 3.0vol) were charged, the mixture was stirred for 2 to 5 minutes and the layers separated. The organic phase was stirred with sat. aq. sodium chloride (5.00L, theta.Ovol) for 25 to 35 minutes, the mixture filtered and the filter-cake washed with ethyl acetate (0.40L, O.deltavol). The filter-cake was retained and the filtrates were transferred to a separating funnel and the layers separated. The procedure was repeated a further 3 times and the retained solids were combined with the organic phase and the mixture concentrated to dryness under vacuum at 35 to 45C. The concentrate was dissolved in propan-2-ol (8.00L, lO.Ovol) at 45 to 55C and activated carbon (0.080Kg, 0.1wt) was charged. The mixture was stirred at 45 to 55C for 30 to 40 minutes and then hot filtered at 45 to 55C. The filter- cake was washed with propan-2-ol (0.40L, 0.5vol). Activated carbon (0.080L, 0.1 wt) was charged to the combined filtrates and wash and the mixture stirred at 45 to 55C for 30 to 40 minutes. The mixture was hot filtered at 45 to 55C and the filter-cake washed with propan-2-ol (0.40L, O.deltavol). The filtrates and wash were concentrated under vacuum at 35 to 45C. Ethyl acetate (8.00, 10.0vol) and water (2.20L, 3.0vol) were charged to the concentrate at 25 to 35C and the mixture stirred for 1 to 2 minutes. The layers were separated and the organic phase was concentrated under vacuum at 35 to 45C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and concentrated under vacuum at 35 to 45C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and the mixture was stirred for 2 to 20 hours at 15 to 250C. The mixture was cooled to and aged at 0 to 5C for 90 to 120 minutes and then filtered. The filter-cake was washed with ethyl acetate (0.80L, 1.Ovol) and pulled dry for 1delta to 30 minutes. The solid was dried under vacuum at 3delta to 4deltaC to yield 1-cyclopropyl-3-[3-(delta-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H- pyrazol-4-yl]-urea (O.delta33Kg, delta6.8%, 93.20% by HPLC area) as a brown solid. |
58.7% | In ethyl acetate; isopropyl alcohol; at 15 - 25℃; for 2 - 24h;Product distribution / selectivity; | Stage 11; Synthesis of l-cvclopropyl-S-rS-CS-mophiholin^-ylmethyl-lH-benzoimidazol^-ylV lH-pyrazol-4-yll-urea L-lactate salt; To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-yhnethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea (9.10 g, 24 mmol) in EtOAc-iPrOH (1:1, 90 mL) was added L-lactic acid (2.25 g, 25 mmol). The mixture was stirred at ambient temperature for 24 h then reduced in vacuo. The residue was given consecutive slurries using toluene (100 mL) and Et2O (100 mL) and the resultant solid collected and dried (8.04 g).This solid was purified by recrystallisation from boiling iPrOH (200 mL) to give after drying 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea, L- lactate salt (5.7 g) as a beige solid.; Stage 11 : Preparation of l-cvclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yll-ureaZ-lactic acid salt; L-Laotic acidC19H23N7O2 C22H29N7O5 FW: 381.44 FW: 471.52 l-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea (1.859Kg, 4.872mol, l.Owt), propan-2-ol (9.00L, 5.0vol) and ethyl acetate (8.00L, 4.5vol) were charged to a flange flask equipped with a mechanical stirrer and thermometer. The contents were stirred under nitrogen and L-lactic acid (0.504Kg, 5.59mol, 0.269wt) was added at 15 to <n="250"/>250C followed by a line rinse of ethyl acetate (0.90L, 0.5vol). The mixture was stirred at 15 to 250C for 120 to 140 minutes. The solid was isolated by filtration, the filter-cake washed with ethyl acetate (2x 2.00L5 2x l.Ovol) and pulled dry for 20 to 40 minutes. The filter-cake was dissolved in ethanol (33.00L, 17.7vol) at 75 to 85C, cooled to 65 to 7O0C and the solution clarified through glass microfibre paper. The filtrates were cooled to and aged at 15 to 250C for 2 to 3 hours. The crystallised solid was isolated by filtration, the filter-cake washed with ethanol (2x 1.00L, 2x 0.5vol) and pulled dry for at least 30 minutes. The solid was dried under vacuum at 35 to 45C to yield l-cyclopropyl-3-[3-(5-morpholin-4-yhnethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-ureaZ-lactic acid salt (1.386Kg, 58.7%th, 99.47% by HPLC area,) as a dark pink uniform solid.1H NMR data (400 MHz, CD3OD) delta 8.08 (s, IH, pyrazole-CH), 7.66 (s, IH, aryl-CH), 7.60 (d, J= 8.0 Hz, IH, aryl-CH), 7.29 (d, J= 8.5 Hz, IH, aryl-CH), 4.15 (q, J= 7.0 Hz, IH, lactate- CH), 3.96 (s, 2H, benzyl-CH2), 3.79 - 3.77 (m, 4H, morpholino-(CH2)2), 2.82 - 2.80 (m, 4H, morpholino-(CH2)2), 2.74 - 2.68 (m, IH, cyclopropyl-CH), 1.38 (d, J= 7.0 Hz, 3H, lactate- CH3), 0.98 (br s, 2H, cyclopropyl-CHa), 0.68 (br s, 2H, cyclopropyl-CH2).The infra-red spectrum of the lactate salt (KBr disc method) included characteristic peaks at 3229, 2972 and 1660 cm"1. |
In methanol; ethyl acetate; at 20℃;Product distribution / selectivity; | To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea (0.7 g, 1.83 mmol) in EtOAc-MeOH was added L-lactic acid (166 mg, 1.85mmol). The mixture was stirred at ambient temperature then reduced in vacuo. This solid was purified by recrystallisation from boiling EtOH (20 niL) to give after drying l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea, L-lactate salt (0.48 g). | |
In methanol; ethyl acetate; at 20℃; | To a solution of 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H- pyrazol-4-yl]-urea (0.7 g, 1.83 mmol) in EtOAc-MeOH was added L-lactic acid (166 mg, 1.85mmol). The mixture was stirred at ambient temperature then reduced in vacuo. This solid was purified by recrystallisation from boiling EtOH (20 ml.) to give after drying 1- <n="289"/>cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-urea, L- lactate salt (0.48 g). | |
at 15 - 25℃; for 2 - 2.33333h; | 1 -Cyclopropyl-3-[3-(5-morpholin-4-yImethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-urea (1.0wt), in a Class 2 or Class 3 solvent in particular a Class 3 solvent such as aqueous ethanol (5.0-10.0 vol), can be charged to a flange flask equipped with a mechanical stirrer and thermometer. The contents are stirred under an inert atmosphere e.g. nitrogen and L- lactic acid (0.269wt) can be added at 15 to 25C followed by a line rinse of the appropriate solvent such as aqueous ethanol (0.5vol). The mixture can be stirred at 15 to 25C for 120 to 140 minutes. The solid may be isolated by filtration or by use of addition of anti-solvent such as n-butanol to bring the salt out of solution and then isolated by filtration. The filter- cake can be washed with the appropriate solvent (2x 2.00L, 2x lOvol) and pulled dry for 20 to 40 minutes. The filter-cake can then be dissolved in a Class 2 or Class 3 solvent in particular a Class 3 solvent (~3-60 vol) at 40 to 1500C1 cooled to 40 to 700C and the solution clarified through glass microfibre paper. The filtrates can be cooled to and aged at 15 to 25C for 2 to 3 hours. The crystallised solid can be isolated by filtration, the filter- cake washed with the appropriate solvent (2x 0.5-2 vol) and pulled dry for at least 30 minutes. The solid can then be dried under vacuum at 35 to 45C to yield 1-cyclopropyl-3- [3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-urea L-lactic acid salt. In addition, alternative methods of purification aside from recrystallisation may be employed for purification of the product such as flash column chromatography or filtration through a plug of silica gel or reverse-phase silica gel. | |
In methanol; ethyl acetate; at 20℃;Product distribution / selectivity; | EXAMPLE 64; Preparation of l-Cvclopropyl-S-fS-fS-Mophiholin^-vhnethyl-lH-Benzoimidazol-?-vD-lH- Pyrazol-4-yl]-Urea lactate salt; To a solution of l-cyclopropyl-S-tS-CS-morpholin^-ylmethyl-lH-benzoimidazol-l-yl)-...- pyrazol-4-yl]-urea (0.7 g, 1.83 mmol) in EtOAc-MeOH was added L-lactic acid (166 mg, 1.85mmol). The mixture was stirred at ambient temperature then reduced in vacuo. This solid was purified by recrystallisation from boiling EtOH (20 mL) to give after drying 1 -cyclopropyl- 3-[3-(5-mophiholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea, L-lactate salt (0.48 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 67.7% 2: 0.6% 3: 24.6% 4: 0.4% | In n-heptane; water at 128℃; for 32h; Heating / reflux; | 1 Esterification: A three-neck flask equipped with a Barrett trap, reflux condenser, thermocouple, heating mantle, and magnetic stirrer is charged with l-menthol (1440 g), L-(+)-lactic acid (2880 g of grade HS-88 from Purac, 88% lactic acid in water), and heptane (720 g). The stirred mixture is brought to reflux and water is periodically drained from the trap as it forms. The temperature of the mixture increases gradually to 128° C. after 32 h and after 854 mL of aqueous phase has been removed. The mixture is cooled to ambient temperature and analyzed by gas-liquid chromatography (GC). It contains: 5.4% of unreacted menthol, 67.7% of l-menthyl L-lactate (ML), 0.6% of lactide (cyclic dimer of lactic acid), 24.6% of l-menthyl L-lactoyl-L-lactate (MLL), and 0.4% of l-menthyl L-lactoyl-L-lactoyl-L-lactate (MLLL).Controlled hydrolysis: The esterified product is diluted with water (4230 g) and heptane (960 g). Aqueous sodium hydroxide (809 g of 50% NaOH) is then added dropwise over 30 min. while the mixture is stirred and cooled (cold water bath) so that the temperature does not exceed 30° C. and the pH does not exceed 12.9. After the base addition, the mixture stirs for another 20 min. GC analysis shows practically complete conversion of MLL into ML. The layers are separated. The organic layer is washed with 1.5% aqueous lactic acid (1000 g) and then cohobated to remove moisture. The solvent (heptane) is stripped, and the residue is fractionally distilled under vacuum with the following results:Fraction 1, 100 g, 94.5% menthol and 2.0% of ML.Fraction 2, 111 g, 46.8% menthol, 51.8% ML.Fraction 3, 1860 g, 99.5% pure ML.Yield of ML contained in all three fractions based on charged menthol: 91%. Yield of purified ML based on reacted menthol: 98%. |
1: 57.6% 2: 0.4% 3: 32.2% 4: 1.9% | In n-heptane at 119℃; for 2h; | 2 Esterification: The procedure of Example 1 is generally followed using 1000 g of l-menthol, 1000 g of L-(+)-lactic acid, 500 g of heptane, and 6 g of concentrated sulfuric acid. The temperature of the mixture increases gradually to 119° C. after 2 h and after 300 mL of aqueous phase has been removed. The mixture is cooled and analyzed by GC. It contains: 6.4% of unreacted menthol, 57.6% of ML, 0.4% of lactide, 32.2% of MLL, and 1.9% of MLLL.Controlled hydrolysis: The esterified product is diluted with water (800 g) and heptane (500 mL). Aqueous sodium hydroxide (204 g of 50% NaOH) is then added dropwise over 70 min. while the mixture is stirred and cooled (cold water bath) so that the temperature does not exceed 30° C. and the pH does not exceed 13.1. The layers are separated. The organic layer is diluted with water (1350 g) and treated with more 50% aq. sodium hydroxide (150 g), which is added dropwise over 1 h in the manner described above. After the base addition, the mixture stirs for about 1 h. GC analysis shows practically complete conversion of MLL into ML. The layers are separated. The organic layer is washed with water.The entire procedure of esterification and controlled hydrolysis is repeated. The washed organic layers are combined, the solvent (heptane) is stripped, and the residue is fractionally distilled under vacuum with the following results:Fraction 1, 203 g, 87.1% menthol, 3.5% ML, and 6.2% menthenes.Fraction 2, 96.8 g, 57.2% menthol, 41.6% ML.Fraction 3, 2356 g, 99.4% pure ML.Yield of ML contained in all three fractions based on charged menthol: 81%. Yield of purified ML based on reacted menthol: 91%. |
1: 48.7% 2: 4.8% 3: 36.5% 4: 5.6% | In n-heptane at 93 - 123℃; for 17h; Heating / reflux; | 3 The esterification procedure of Example 1 is generally followed using 1000 g of l-menthol, 2000 g of L-(+)-lactic acid, 500 g of heptane, and 10 g of crystalline NaHSO4.H2O. The reflux starts at about 93° C. and finishes at about 123° C. after about 581 g of the water is drained, which takes slightly under 17 h. Composition of the mixture (%, GC): menthol 3.3%, ML 48.7%, lactide 4.8%, MLL 36.5%, MLLL 5.6%. The mixture is then used in the hydrolysis experiments described below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | (S)-7-Amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one (50 mg, 0.14 mmol) and L-(+)-lactic acid (14 mg, 0.15 mmol) were dissolved in THF (2 ml), cooled to 0 C. and under exclusion of moisture subsequently treated with 1-hydroxybenzotriazole (21 mg, 0.15 mmol), EDC (33 mg, 0.17 mmol) and N-diisopropyl-ethylamine (0.05 ml, 0.28 mmol). After stirring for 30 min. at 0 C. and 3 h at ambient temperature, the mixture was diluted with water and ethyl acetate (10 ml each), the phases separated and the organic layer extracted with water, 1N aqueous HCl and saturated aqueous NaCl. After drying over magnesium sulphate and evaporation of the solvent, the title compound was afforded as colourless oil (98%). MS: m/e=431 (M-H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;dmap; In dichloromethane; at 20℃; for 3h; | N-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidm-4-yl)-l,2,4- thiadiazol-5-amine (Example 34, Step C, 0.075 g, 0.16 mmol), (S)-2-hydroxypropanoic acid (0.018 g, 0.19 mmol), Nl-((ethylimino)memylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (0.047 g, 0.24 mmol), and N,N-dimethylpyridin-4-amine (0.002 g, 0.016 mmol) were dissolved in CH2Cl2 (5 mL). Triethylamine (0.033 g, 0.32 mmol) was added and the solution was stirred at ambient temperature for 3 hours. Water was added and extracted with CH2Cl2, dried, filtered, and concentrated. The residue was purified by silica gel (1-2% MeOH in CH2Cl2) to give (R)-2-hydroxy-l-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2- ylamino)-l,2,4-thiadiazol-3-yl)piperidin-l-yl)propan-l-one (0.023 g, 27% yield). 1H NMR <n="66"/>(d6-DMSO) delta 12.34 (s, IH), 8.39 (d, IH), 8.37 (m, IH), 7.66 (dt, IH)5 7.47 (d, IH)3 7.42 (t, 2H), 7.21-7.11 (m, 5H), 4.82 (t, IH), 4.45 (m, IH), 4.34 (m, IH), 4.01 (m, IH), 3.25-3.04 (m, 2H), 2.84 (m, IH), 2.02 (d, 2H), 1.81-1.55 (m, 2H), 1.18 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In ethanol;Product distribution / selectivity; | The product of Step 12 (646 g, 1.58 mol) was dissolved in ethanol (5.17 L) and the solution filtered. A solution of L-lactic acid (142 g, 1.58 mol) dissolved in ethanol (2.59 L) was filtered and added to the solution of the filtered solution (above) and then to the mixture was added EtOAc (7.75 L). The suspension was stirred at RT for 12 h and then cooled to 5 0C for a further 2h. The solid which had formed was removed by filtration, washed with EtOAc (2 x 2.58 L) and heptane (2 x 1.94 L) and dried to constant weight at 35 0C giving the title compound (581 g, 74 % yield). |
In ethanol; ethyl acetate; | The product of Example 1 (1.24 g, 3.303 mmol) was suspended in ethanol (3 mL) and EtOAc (5 mL) and a solution of L-lactic acid (0.285 g, 3.13 mmol) dissolved in ethanol (3 mL) was added. The solution was heated until clear and then was filtered. EtOAc (5 mL) was used to wash the filter and the combined filtrates were stirred at RT for 2 h with seeding. The crystalline mass which formed was removed by filtration, was washed with EtOAc and then dried in vacuum at 5O0C to give the title compound 1.29 g.1 H NMR (400 MHz, Me-d3-OD): 7.30 (s, 3H), 7.18 (s, 1H), 6.39 (s, 1 H), 4.91 (s,4H), 4.08 (q, J = 6.8 Hz, 1H), 3.70-3.63 (m, 2H), 3.28-3.15 (m, 1H), 3.01 (s, 4H), 2.68 (m, 7H), 1.36 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.9 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.4 - 83.9% | 37.9g (-0. 6 mol) pulverized potassium hydroxide (>85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100g (0.196 mol) <strong>[82640-04-8]raloxifene hydrochloride</strong> is added in small portions in such a way that temperature is kept below [30 C.] After addition of <strong>[82640-04-8]raloxifene hydrochloride</strong>, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. A solution of 67.6 g 85% L-lactic acid (0.6 mol) is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white/yellowish crystals. The product is now washed 2 times with 40 ml 2-propanol and then dried in vacuo at [55-65 C] for 16 hours to give 109 g crude product. The crude product is stirred with 545 ml of water for 3 hours and then filtered off and washed 2 times with 75 ml of water. The product is dried in vacuo at 75- 80 [C] for 16 hours to give 92.7g (83.9% yield) of product. Mp:. [134-136C] Elemental analysis C31H33NO7S (½H2O) : Calculated: C: 65.00 % H: 5.98 % N: 2.45 % S: 5.60 % Found: C: 65.08% H: 6.14 % N: 2.58 % S: 5.78 % IR: 3167 [CM ~,] 2934 [CM'1,] 1641 cm-1, 1627 cm-, 1593 cm'1, 1543 cm-1, 1500 [CM'1,] 1469 cm'1, 1433 cm'1, 1350 [CM'1,] 1314 cm 1259 cm 1170 cm 1128 cm'1, 1103 [CM'',] 1033 [CM ~,] 908 cm-1, 836 cm 809 cm The product was analysed using differential scanning calorimetry using a MET- TLER TOLEDO [STAR&COMMAT; ] system, according to the instructions of the manufac- turer. The differential scanning calorimetric chart (DSC) is shown in figure 3. Further the product was analysed by X-ray diffraction analysis using the STOE Powder diffraction system. The result is shown in figure 4, and is also listed numerically below. XRD: [D 2THETA I (REL) I (ABS)] FWHM 14.639874 6.0322 17.56 6122 0.1200 13.207421 6.6871 15.07 5254 0.1200 10.875932 8.1229 80.41 28029 0.1200 9.268456 9.5347 22.67 7903 0.1200 8.140638 10.8593 17.92 6247 0.1200 7.488503 11.8083 15.59 5433 0.1000 7.310331 12.0971 12.47 4347 0.0800 7.089508 12.4754 25.79 8991 0.1000 6.931874 12.7603 12.78 4454 0.0900 6.723932 13.1566 27.83 9701 0.1300 6.551458 13.5045 14.20 4949 0.0900 6.359432 13.9143 30.57 10656 0.1100 6.130010 14.4378 21.33 7435 0.1300 5.853018 15.1249 36.40 12687 0.1100 5.626204 15.7385 15.49 5401 0.1300 5.507643 16.0795 23.25 8106 0.1000 5.447238 16.2590 13.21 4606 0.0870 5.224449 16.9573 19.21 6697 0.1100 5.160516 17.1690 17.10 5961 0.0870 5.083475 17.4312 14.74 5137 0.1100 4.954247 17.8896 19.64 6848 0.1000 4.863750 18.2252 28.34 9879 0.0800 4.805168 18.4494 46.26 16125 0.0700 4.756883 18.6383 49.99 17425 0.0800 4.656926 19.0420 19.10 6659 0.1900 4.630194 19.1530 17.96 6260 0.0870 4.566015 19.4248 21.34 7438 0.1000 4.487514 19.7680 12.76 4447 0.1000 4.347753 20.4101 11.69 4074 0.1100 4.301465 20.6322 19.17 6682 0.0900 4.224555 21.0120 14.55 5072 0.0870 4.186561 21.2049 23.33 8134 0.1700 4.065767 21.8425 26.06 9084 0.1000 4.015560 22.1190 17.10 5929 0.1000 3.976949 22.3365 14.98 5223 0.0500 3.935785 22.5732 34.50 12028 0.1100 3.867038 22.9799 100.00 34859 0.1000 3.779481 23.5198 40.14 13991 0.0800 3.742319 23.7567 59.68 20805 0.1000 3.710418 23.9640 13.17 4591 0.0870 3.645564 24.3968 11.19 3902 0.0800 3.621808 24.5593 18.71 6524 0.1000 3.552536 25.0459 16.01 5581 0.1000 3.516088 25.3098 13.46 4691 0.0600 3.498357 25.4402 12.66 4413 0.0700 3.467075 25.6737 10.74 3745 0.0500 3.418947 26.0414 21.49 7491 0.1000 3.395298 26.2260 12.12 4225 0.0870 3.369948 26.4268 15.48 5369 0.0700 3.358554 26.5181 14.33 4995 0.0600 3.244985 27.4641 11.90 4149 0.0700 3.229427 27.5990 9.63 3356 0.0870 3.177657 28.0578 15.07 5253 0.1200 3.144884 28.3562 32.65 11381 0.1000 3.106130 28.7176 9.83 3425 0.0800 3.082970 28.9380 9.00 3138 0.0870 3.056106 29.1980 8.56 2984 0.0870 3.032184 29.4335 8.74 3048 0.1100 2.994539 29.8121 8.27 2884 0.0700 2.979114 29.9700 9.26 3229 0.0800 2.924922 30.5387 9.19 3203 0.1800 2.870290 31.1346 16.32 5689 0.1400 2.828902 31.6019 13.59 4737 0.1100 2.762611 32.3808 10.83 3775 0.1000; Example 6 [L6-HVDROXV-2-(4-HYDROXYPHENYL) BENZOLBLTHIEN-3-YLL L4-L2-(1-] [PIPERIDINYL) ETHOXYLPHENYL-, ;] Raloxifene L-lactate [(1/4] H2O). 37.9g (-0. 6 mol) pulverized potassium hydroxide (>85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100g (0.196 mol) <strong>[82640-04-8]raloxifene hydrochloride</strong> is added in small portions in such a way that temperature is kept below [30 C.] After addition of <strong>[82640-04-8]raloxifene hydrochloride</strong>, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. A solution of 67.6g 85% L-lactic acid (0.6 mol) is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours. If no or very little precipitate appears in the solution the reaction mix- ture is filtered and 2-pro... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 145 - 185℃; for 10.5h; | 1 500 ml of L-lactic acid (to which D-lactic acid was also mixed) was placed into a separable flask in a mantle heater. 300 ml/min of nitrogen gas was flowed therein while stirring. Accumulated water was introduced into a flask equipped with a reflux condenser via a warmed descending type connecting tube, while heating at 145° C. for 3 hours. Furthermore, after pressure was reduced to 150 mmHg and heated at the same temperature for 3 hours, the mixture was heated at 155° C. for 3 hours under a reduced pressure of 3 mmHg, and then at 185° C. for 1.5 hours under a reduced pressure of 3 mmHg to obtain poly lactic acids as a reaction product. The obtained poly lactic acids were kept at 100° C., and 100 ml of ethanol and 400 ml of methanol were separately added thereto, and then the mixture was allowed to be cooled. This mixture was added to 500 ml of methanol, and the mixture was well stirred and left to stand. Then, the mixture was filtrated for purification. The filtrate was subjected to vacuum drying and then dissolved in acetonitrile to obtain 200 ml (stock solution) in total. The stock solution was subjected to a reverse phase ODS column (TSK gel ODS-80) which was previously equilibrated, and was stepwise eluted with 30%, 50% and 100% acetonitrile (pH2.0) each containing 0.01M hydrochloric acid to obtain poly lactic acids (condensation degree of 3 to 20) as an acetonitrile 100% elution fraction. The mass spectrum of the obtained substance is shown in FIG. 1. As is clear from the regular fragment ion peaks in FIG. 1, the obtained mixture of poly lactic acids comprises cyclic condensate and a linear condensate in a mixed state. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -5 - 20℃;Inert atmosphere; | Under argon, 100 g (0.892 mol) of 4- fluorophenol (2) was combined with 105.2 g (0.892 mol) of (S)-ethyl lactate and 233.8 g (0.892 mol) of triphenylphosphine in 1200 mL of tetrahydrofuran (THF). The reaction mixture was cooled to -50C, and 180.4 g (0.892 mol) of diisopropylazodicarboxylate (DIAD) in 500 ml of THF was dropwise added. The ice bath was removed, and stirring was continued at room temperature for 18-22 hr. THF was then evaporated in vacuo, and 1400 mL of hexane-ether (80:20) was added to the residue, and the remaining solid was removed by filtration. The filtrate was then washed with 2 x 600 mL of IN NaOH, followed by 2 x 600 mL of water and 600 mL of brine. The washed filtrate was then dried over MgSO4, filtered and then evaporated to give 185 g of (/?)-ethyl-2-(4-fluorophenoxy)-propionate, 7, as a light yellow oil in 98% yield, Bp 800C at 0.7 mm Hg. The reaction is shown as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A lactide/polylactide manufacturing system as schematically diagrammed in Figure 1 is operated. A fresh stream of a 64% lactic acid solution in water is fed into prepolymer reactor 1 through line 5. The lactic acid in this stream is 99.8% S-lactic acid and 0.2% R-lactic acid. An overhead stream is taken from prepolymer reactor 1 through line 7. Prepolymer is transferred through line 6 to lactide reactor 2, with addition of catalyst through line 18. A purge stream is taken from lactide reactor 2 through line 9. Crude lactide is taken via line 8 to first distillation column 3. An overhead stream, which contains most of the water and lactic acid contained in the crude lactide, together with a small amount of lactide and some linear lactic acid oligomers, is taken from first distillation column 3 through line 12; the contents of that stream are combined with the fresh lactic acid stream entering prepolymer reactor 1 through line 5, and recycled in that manner. Partially purified crude lactide is transferred to second distillation column 4 through line 10. An overhead stream is taken from second distillation column 4 through line 22, and a bottoms stream is taken through line 11. The overhead stream contains mainly water, lactic acid or linear lactic acid oligomers, and some lactide.A purified crude lactide steam is transferred to third distillation column 20 via line 21, where meso-lactide is separated from S,S- and R,R-lactide. A product stream is taken from third distillation column 20 via line 13. The separation is made so that the R-enantiomer content of product stream 13 is 1.5%. This product stream is polymerized in polymerization unit 23 to produce polylactide stream 13A. The polymerized product is devolatilized to produce devolatilization stream 24. Stream 24 is combined with streams 11 and 22, and they are recycled together into lactide reactor 2 via line 19.A meso-lactide stream is taken from third distillation column 20 via line 14. No intermediate-boiling impurities stream 15 or purge stream 16 is taken.Conditions in the prepolymer reactor are: pressure of about 80 mm Hg; temperature of 17O0C and average residence time of about 3 hours. Conditions in the lactide reactor are 22O0C, 10-15 mm Hg pressure, 1500 ppm tin catalyst, residence time 30-60 minutes.In Comparative Run A, the meso-lactide stream is removed from the system and discarded. Flows through the system in this case are as follows: In Example 1, 0.45 mass units/hour of the meso-lactide stream 14 are recycled into lactide reactor 2 via line 14A, such that the lactide becomes reincorp orated into the prepolymer. The conditions in the lactide reactor are sufficient to obtain a nearly random distribution of the recycled meso-lactide in the prepolymer. This increases the amount of R-enantiomer in the prepolymer which in turn increases the mole fractions of meso-lactide and R,R-lactide in the crude lactide stream. Flows in this case are as follows: Example 1 flowsIn each of Comparative Run A and Example 1, the lactide product stream which is taken to polymerization contains 1.5% of R-lactic units. However, the composition of the lactide product stream is different in the two cases, as follows:Yield to polymer is slightly higher in Example 1 (21.9/25.2 = 86.9%) than in Comparative Run A (21.8/25.2 = 86.5%). In comparative Run A, 4.4% of the meso-lactide produced remains in the lactide product stream 13, whereas in Example 1, essentially none of the meso- lactide that is produced exits the system with product lactide stream 13. Because the meso-lactide is more completely separated in Example 1, the product lactide stream in that case contains fewer intermediate-boiling impurities than in Comparative Run A. In Comparative Run A, the intermediate-boiling impurities removed with meso-lactide stream 14 are purged from the system because that stream is discarded. In the Example 1 case, those impurities are recycled with the meso-lactide stream. Their accumulation in the system can be prevented by adjusting the volumes of purge streams such as streams 7, 9 and 16.Note that in Example 1, the amount of meso-lactide that is recycled is smaller than the meso-lactide stream that is taken from third distillation column 20. The recycle stream in this case constitutes about 20% of the mass of the meso-lactide stream, meaning losses from the meso-lactide stream are reduced by at least that amount. | ||
With potassium hydroxide;stannous octoate; at 150 - 240℃; under 7.50075 Torr;Product distribution / selectivity; | A distillation structure was filled with 396.8 g L-LAC and 2.93 g KOH. After removing water by means of a vacuum, 0.506 g SnOc2 was added; the temperature was increased from 150 C. to 240 C. and the pressure was lowered to 10 mbar. Three fractions which were collected in a temperature range of 100 C. to 150 C. contain the compounds. The total yield was 46% (L-LA:D-LA:M-LA=54:18:28). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 6h; | A mixture of 8-bromo-1 -(piperidin-4-yl)-[1 ,2,4]triazolo[4,3-a]quinoxaline (250 mg, 0.75 mmol), (S)-2-hydroxypropanoic acid (75 mg, 0.83 mmol), HATU (346 mg, 0.90 mmol), and DIEA (1 16 mg, 0.90 mmol) in DMF (5 ml_) was stirred at r.t. for 6h. Then the solvents was removed, and the residue was purified by ISCO(MeOH/H2O=20%-90%) to afford (S)-1 -(4-(8-bromo-[1 ,2,4]triazolo[4,3-a]quinoxalin-1 - yl) piperidin-1 -yl) -2-hydroxypropan-1 -one as pale yellow solid (200 mg, yield 66.0%). MS (m/z): 404 (M+H)+. |
66% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 6h; | A mixture of 8-bromo-1-(piperidin-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline (250 mg, 0.75 mmol), (S)-2-hydroxypropanoic acid (75 mg, 0.83 mmol), HATU (346 mg, 0.90 mmol), and DIEA (116 mg, 0.90 mmol) in DMF (5 mL) was stirred at r.t. for 6 h. Then the solvents was removed, and the residue was purified by ISCO (MeOH/H2O=20%-90%) to afford (S)-1-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one as pale yellow solid (200 mg, yield 66.0%). MS (m/z): 404 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.7% | In water; butan-1-ol; at 50 - 60℃;Resolution of racemate; | Two grams (2 g, 15.6 mmol) of <strong>[4138-26-5]nipecotamide</strong> was dissolved in 10 mL of 1-butanol. To the solution was added 1.76 g ([alpha]D20=-13° (c=2.5, 1.5 mol/L NaOH), 85percent aqueous solution, 16.6 mmol) of L-lactic acid, and the solution was stirred at 50° C. To the reaction mixture was added a small amount of L-lactic acid salt of S-<strong>[4138-26-5]nipecotamide</strong>, which was prepared in advance, as a seed crystal, and a diastereomer salt was precipitated. The reaction mixture was stirred for 1 hour at 60° C., then was left to cool to room temperature while stirring, and was further stirred at the same temperature overnight. The precipitated diastereomer salt was filtered and collected, and was washed with 5 mL of 1-butanol. After drying, the obtained white diastereomer salt weighed 1.25 g. The diastereomer salt was L-lactic acid salt of S-<strong>[4138-26-5]nipecotamide</strong>, and the yield was 36.7percent. The optical purity of S-<strong>[4138-26-5]nipecotamide</strong> obtained from the diastereomer salt was analyzed and was found to be 99.0percent ee.1H-NMR (DMSO-d6, 400 MHz) deltappm: 7.47 (1H, s), 6.95 (1H, s), 3.71 (1H, q, J=13.7, 6.8 Hz), 3.14-3.02 (2H, m), 2.80-2.64 (2H, m), 2.54-2.44 (1H, m), 1.90-1.84 (1H, m), 1.74-1.67 (1H, m), 1.62-1.43 (2H, m), 1.14 (3H, d, J=6.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine; dmap; In tetrahydrofuran; at 75℃; for 24h;Inert atmosphere; | Preparation of (S)-2-(((S)-2-((tert-Butoxycarbonyl)amino)propanoyl)oxy)propanoic acid (S)-Lactic acid (944 mg, 10.5 mmol), (S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)propanoate (2.50 g, 8.73 mmol), 4-(dimethylamino)pyridine (107 mg, 0.873 mmol), pyridine (831 mg, 10.5 mmol), and tetrahydrofuran (40 mL) were combined and heated at 75 C. under a nitrogen atmosphere for 24 h. After this time, the solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate (20 ml). The aqueous phase was collected and acidified to pH=2 with 6 N hydrochloric acid, and the mixture was extracted with ethyl acetate (2*20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoic acid (2.10 g, 92%) as a colorless oil: 1H NMR (300 MHz, CDCl3) delta 5.19 (t, J=6.9 Hz, 1H), 5.01 (m, 1H), 4.35 (m, 1H), 1.56 (d, J=7.2 Hz, 3H), 1.46-1.43 (s, 12H), CO2H proton not observed. |
dmap; In tetrahydrofuran; pyridine; at 20 - 25℃; for 72h; | [0190] 1. Preparation of Boc-L-Ala-Lac-OH (9) DCHA salt9 9 DCHAsalt [0191] A 2 L flask was charged with L-lactic acid (37.8 g, 419 mmol, 1.2 equiv.), DMAP (5.1 g, 41.9 mmol, 0.1 equiv.) and Boc-Ala-OSu (100 g, 349 mmol, 1.0 equiv.), followed by THF (750 mL) and pyridine (33.2 mL, 419 mmol, 1.2 equiv.). The thin cloudy slurry was stirred at 20-25 C for 72 h, during which time the mixture became clear and nearly colorless. The reaction was checked by 1H NMR: an aliquot (1 mL) of the reaction mixture was concentrated to dryness and part of the crude sample (20-30 mg) was dissolved in CDC13 (1 mL). Upon completion, the reaction mixture was concentrated to near dryness (the total weight of 364 g), dissolved in MTBE (600 mL) and concentrated again to the total weight of 372 g. This cycle was repeated one more time (the total weight of 356 g) in order to minimize the residual THF which will help to prevent yield loss. The resulting residue was dissolved in MTBE (300 mL) and the pH of the slurry was adjusted to ~3 by addition of 0.5 N HC1 (400 mL) resulting in a slight exotherm (20.6 to 24.6 C). The layers were separated and the MTBE layer was washed with 0.5 N HC1 (400 mL, pH 0-1). The two acidic aqueous layers (the weight of aqueous layers 1 and 2, 466 g and 431 g, respectively) were combined and back extracted with MTBE (200 mL) (Note 1 and 2).[0192] Note 1 : If the MTBE layer is held at ambient temperature for too long under these acidic conditions, solids (Boc-Ala impurity) will precipitate. If only a small amount of solid is formed, this solid rag layer can be carried along with the organic MTBE layer in the following step. Otherwise the entire solution, or part of the solution, can be filtered and the filtered solids rinsed with a small amount of MTBE.[0193] Note 2: The MTBE (500 mL) from the following step or a portion of this may be added to the organic layer at this stage if necessary.[0194] The combined MTBE layers were washed with deionized water (400 mL) and 20% aqueous NaCl (400 mL): the weight of water and brine layers was 411 g and 446 g, respectively. The layers were separated and the organic layer was diluted with MTBE (500 mL).Dicyclohexylamine (47.8 g, 0.75 equiv) was then added to the clear solution over ~10 min at 20- 25 C to reach a pH of 7 (exotherm to 26 C) (Note 3).[0195] Note 3 : The amount of required dicyclhexylamine to make a pH of 7 will vary depending on the degree of completion of the reaction.[0196] Crystallization occurred after dicyclohexylamine was added and the mixture (may be either clear or cloudy) became a thick white slurry. The thick slurry was heated to 30 C, at which temperature both good stirring and good recovery was achieved. The mixture was filtered using recycled filtrate, washed with MTBE (2 x 100 mL), and dried in a vacuum oven at 40-45 C until a constant weight (61 g) was obtained.[0197] Recrystallization: A 3L flask was charged with crude 9 DCHA salt (61 g), MTBE (1525 mL) and water (61 mL). The slurry was heated to 50-55 C to dissolve all solids and stirred at 52-53 C for about 1 h. The mixture should form a clear solution in which solids are not visible (Note 4).[0198] Note 4: If about 95% of the solids have truly gone into solution (based on visual inspection), leaving it a little cloudy, the solution is allowed to cool. The MTBE to water ratio is critical for complete dissolution.[0199] The resulting clear solution was cooled to 0-5 C and held at the same temperature for at least 1 h. Solids began to precipitate between temperatures of 35 C and 45 C. The precipitates were collected by filtration and washed with MTBE (61 mL). The wet cake (82 g) was dried in a vacuum oven at 45 C until constant weight was achieved (solid density = 0.1 g / mL) (Note 5).[0200] Note 5 : The reaction of 9 DCHA salt with compound 8 was carried out on a small scale (400 mg of compound 8) to determine the purity of 9. Thus, compound 10 containing less than 0.5% of the alanine lactate ester-amide 10-1 was obtained by use of compound 9 DCHA salt being recrystallized two times. Higher purity 9 DCHA salt can be obtained by repeated recrystallizations as described above.[0201] 1 H NMR (400 MHz, DMSO-d6) delta 7.19 (d, J = 7.2 Hz, 1H), 4.68 (q, J = 6.8 Hz, 1H), 3.96 (m, 1H), 2.96-2.82 (m, 2H), 1.96-1.87 (m, 4H), 1.76-1.67 (m, 4H), 1.62-1.55 (m, 2H), 1.37 (s, 9H), 1.28 (d, J = 7.2 Hz, 3H), 1.27-1.18 (m, 11H), 1.14-1.12 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.9% | In dichloromethane for 0.0833333h; Reflux; | 9.c (c) Alternatively, GW572016X (3.0 g) was heated to reflux in DCM (120 ml). L-lactic acid (0.95 g) was added to the warm solution which was stirred at reflux for 5 minutes then allowed to cool. The solution turned cloudy and oil separated. After 30 minutes the mixture was seeded with the product from example 9(b). The oil solidified and more solid was precipitated. The suspension was stirred at ambient temperature for 48 hours. The product was filtered and dried under vacuum at 400C for 3 hours to give the title salt. (3.18g, 80.9% yield) An X-ray powder diffraction pattern and an infrared spectrum were obtained and are depicted in Figure 9(a) and Figure 9(b) respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.9% | In acetonitrile at 20 - 60℃; | 10 Preparation of Lapatinib mono-L-lactateA mixture of GW572016X (1.0 g) and L-lactic acid (0.2 g) was heated to 60°C in acetonitrile (20 ml) so that a clear solution was obtained. The solution was allowed to cool and as the temperature dropped below 400C crystals began to precipitate. The resulting suspension was stirred at ambient temperature for 1 hour then left to stand overnight. The product was filtered, washed with acetonitrile and dried under vacuum at 40°C overnight to give the title salt. (0.9 g, 77.9% yield) An X-ray powder diffraction pattern and an infrared spectrum were obtained and are depicted in Figure 10(a) and Figure 10(b) respectively |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With marine microbial esterase; In aq. phosphate buffer; at 37℃; for 1h;pH 7.5;Resolution of racemate; Enzymatic reaction; | A standard 500-muL hydrolytic reaction system containing140 mug purified esterase PHE14, 50 mmol/L substrate (racemicmethyl lactate) and 50 mmol/L phosphate buffer (pH 7.5) wasincubated at 37 C for 1 h. After the completion of the enzymaticreaction, reaction samples were extracted with an equalvolume of ethyl acetate and the organic phase was further analyzedto evaluate the enzymatic resolution of (±)-methyl lactate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With hydrogenchloride; In water; at 100℃; for 18h;Sealed tube; | Step 2: synthesis of (1 S)- 1- [5-chloro- 1- (3,3,3 -trifluoropropyl)- 1 H-benzimidazol-2-yl] ethanol A mixture of 4-chloro-N?-(3,3,3-trifluoropropyl)benzene-1,2-diamine (478 mg, 2.0 mmol) and Llactic acid (180 mg, 2.0 mmol) in 6 N aqueous HC1 (4 mL) was heated with stirring at 100 C in a sealed tube for 18 hours. After the reaction was complete, the mixture was poured into aqueousammonia (10 mL) and then extracted by EtOAc (25mL x 3). The organic layers were combined and then concentrated in vacuo. The residue was purified by flash column chromatography to afford (1 S)- 1- [5-chloro- 1- (3,3 ,3-trifluoropropyl)- 1 H-benzimidazol-2-yl] ethanol as yellow oil (320 mg, yield 63.0%). |
63.0% | With hydrogenchloride; In water; at 100℃; for 18h;Sealed tube; | Step 2: synthesis of (1S)-1-[5-chloro-1-(3,3,3-trifluoropropyl)-1H-benzimidazol-2-yl]ethanol A mixture of 4-chloro-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine (478 mg, 2.0 mmol) and L-lactic acid (180 mg, 2.0 mmol) in 6 N aqueous HCl (4 mL) was heated with stirring at 100 C. in a sealed tube for 18 hours. After the reaction was complete, the mixture was poured into aqueous ammonia (10 mL) and then extracted by EtOAc (25 mL*3). The organic layers were combined and then concentrated in vacuo. The residue was purified by flash column chromatography to afford (1S)-1-[5-chloro-1-(3,3,3-trifluoropropyl)-1H-benzimidazol-2-yl]ethanol as yellow oil (320 mg, yield 63.0%). |
63% | With hydrogenchloride; In water; at 100℃; for 18h;Sealed tube; | A mixture of 4-chloro-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine (478 mg, 2.0 mmol) and L-lactic acid (180 mg, 2.0 mmol) in 6 N aqueous HCl (4 mL) was heated with stirring at 100 C. in a sealed tube for 18 hours. After the reaction was complete, the mixture was poured into aqueous ammonia (10 mL) and then extracted by EtOAc (25 mL×3). The organic layers were combined and then concentrated in vacuo. The residue was purified by flash column chromatography to afford (1S)-1-[5-chloro-1-(3,3,3-trifluoropropyl)-1H-benzimidazol-2-yl]ethanol as yellow oil (320 mg, yield 63.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap In acetonitrile at 70℃; for 8h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 43.39% 2: 22.95% 3: 7.4% | With sulfuric acid In n-heptane at 120℃; for 7h; | 2 Example 2 Preparation of composition of menthol and menthyl lactate by acid catalyzed esterification and controlled hydrolysis followed by Fractional distillation Example 2 Preparation of composition of menthol and menthyl lactate by acid catalyzed esterification and controlled hydrolysis followed by Fractional distillation Esterification: The procedure of Example 1 is generally followed using L-menthol (20 g, 0.128 mol), L-(+)-lactic acid (20 g, 0.195 mol, 88 %, pure), heptane (10 g) and cone. H2S04 (0.12 g). The temperature of the mixture increases gradually to 120 °C after 7 h and after 4.8 ml water was removed and about 20 % menthol remained unreacted. The mixture was cooled to room temperature and analyzed by gas chromatography (GC). It contains: 20.79 % unreacted menthol, 43.39 % of ML, 22.95 % of MLL, 7.40 % of MLLL and some lactide. Controlled hydrolysis: The partially esterified mixture is diluted with water (16 g) and heptane (15 ml). Aq. Sodium hydroxide (9.3 g of 50 % NaOH) was then added drop wise over 30 min. under external cooling (cold water bath) so that the temperature does not exceed 30 °C and the pH does not exceed 12.5. After the base addition, mixture was stirred for another 2.5 h. pH was 12. GC analysis shows practically complete conversion MLL and MLLL into ML. GC shows: 22.60 % of unreacted menthol, 75.44 % of ML and 0.52 % of MLL. The layers were separated. The organic layer washed with water (20 g) and then dried over sodium sulfate. The solvent removed on Rota vapor to get the residue (23 g) Fractional Distillation: Residue (23 g) was fractionally distilled using Perkin Triangle under constant vacuum at 5 mbar and obtained the following fractions |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; hydrogen at 210℃; for 1h; | Cellulose reaction General procedure: Cellulose (microcrystalline, Alfa Aesar) reactions were carried out in a stainless steel autoclave (100mL) typically at 210°C and 6MPa H2 for 30min with vigorous stirring at a speed of 800rpm. In a typical run, 1g cellulose and 0.4g catalyst were introduced into the autoclave containing 50mL H2O. Afterwards, the reactor was fully purged with H2 (>99.999%, Beijing Longhui Jingcheng), pressurized with H2 to 6.0MPa and then heated to 210°C which was kept constant during the reaction. After cooling to room temperature in water, the reaction mixture was filtrated and the solids were washed several times with deionized water. The solids including the catalyst and remaining cellulose were washed with acetone three times and then fully dried in an oven at 60°C for 24h. Cellulose conversions were determined by the change in the weight of cellulose loaded before and after the reactions. The products in the liquid phase (e.g. polyols) were analyzed by high-performance liquid chromatography (Shimadzu LC-20A) using Bio-Rad Aminex HPX-87H with a RID detector. The product selectivities were reported on a carbon basis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; hydrogen at 210℃; for 0.5h; Autoclave; | Cellulose reaction General procedure: Cellulose (microcrystalline, Alfa Aesar) reactions were carried out in a stainless steel autoclave (100mL) typically at 210°C and 6MPa H2 for 30min with vigorous stirring at a speed of 800rpm. In a typical run, 1g cellulose and 0.4g catalyst were introduced into the autoclave containing 50mL H2O. Afterwards, the reactor was fully purged with H2 (>99.999%, Beijing Longhui Jingcheng), pressurized with H2 to 6.0MPa and then heated to 210°C which was kept constant during the reaction. After cooling to room temperature in water, the reaction mixture was filtrated and the solids were washed several times with deionized water. The solids including the catalyst and remaining cellulose were washed with acetone three times and then fully dried in an oven at 60°C for 24h. Cellulose conversions were determined by the change in the weight of cellulose loaded before and after the reactions. The products in the liquid phase (e.g. polyols) were analyzed by high-performance liquid chromatography (Shimadzu LC-20A) using Bio-Rad Aminex HPX-87H with a RID detector. The product selectivities were reported on a carbon basis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; hydrogen at 210℃; for 0.5h; Autoclave; | Cellulose reaction General procedure: Cellulose (microcrystalline, Alfa Aesar) reactions were carried out in a stainless steel autoclave (100mL) typically at 210°C and 6MPa H2 for 30min with vigorous stirring at a speed of 800rpm. In a typical run, 1g cellulose and 0.4g catalyst were introduced into the autoclave containing 50mL H2O. Afterwards, the reactor was fully purged with H2 (>99.999%, Beijing Longhui Jingcheng), pressurized with H2 to 6.0MPa and then heated to 210°C which was kept constant during the reaction. After cooling to room temperature in water, the reaction mixture was filtrated and the solids were washed several times with deionized water. The solids including the catalyst and remaining cellulose were washed with acetone three times and then fully dried in an oven at 60°C for 24h. Cellulose conversions were determined by the change in the weight of cellulose loaded before and after the reactions. The products in the liquid phase (e.g. polyols) were analyzed by high-performance liquid chromatography (Shimadzu LC-20A) using Bio-Rad Aminex HPX-87H with a RID detector. The product selectivities were reported on a carbon basis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; hydrogen at 200℃; for 0.5h; Autoclave; | Cellulose reaction General procedure: Cellulose (microcrystalline, Alfa Aesar) reactions were carried out in a stainless steel autoclave (100mL) typically at 210°C and 6MPa H2 for 30min with vigorous stirring at a speed of 800rpm. In a typical run, 1g cellulose and 0.4g catalyst were introduced into the autoclave containing 50mL H2O. Afterwards, the reactor was fully purged with H2 (>99.999%, Beijing Longhui Jingcheng), pressurized with H2 to 6.0MPa and then heated to 210°C which was kept constant during the reaction. After cooling to room temperature in water, the reaction mixture was filtrated and the solids were washed several times with deionized water. The solids including the catalyst and remaining cellulose were washed with acetone three times and then fully dried in an oven at 60°C for 24h. Cellulose conversions were determined by the change in the weight of cellulose loaded before and after the reactions. The products in the liquid phase (e.g. polyols) were analyzed by high-performance liquid chromatography (Shimadzu LC-20A) using Bio-Rad Aminex HPX-87H with a RID detector. The product selectivities were reported on a carbon basis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.5%Chromat.; 23.8%Chromat.; 29%Chromat. | With H-BEA; In o-xylene; for 3h;Dean-Stark; Heating; | Equimolar amounts of D-2-hydroxybutyric acid and L-lactic acid were mixed in o-xylene and reacted in the presence of H-BEA (Si/AI2: 25) (0.25 g) at an oil bath temperature of 170C. A Dean-Stark trap was used for removal of water from the reaction mixture. After 3 h of reaction, the products as listed in Table 5 were obtained, as measured by H1-NMR and confirmed by GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; calcium hydroxide at 199.84℃; for 1h; Autoclave; | General procedure: Xylitol hydrogenolysis reactions were carried out in a stainlesssteel autoclave (100 ml) at a stirring speed of 800 rpm. Typically,40 g of 10 wt% xylitol (99%, Alfa Aesar) aqueous solution, properamount of Ni catalysts (varied depending on xylitol conversion)and also for the Ni/C case, solid base were introduced to the auto-clave. Afterwards, the reactor was purged with H2(>99.99%, BeijingHuayuan) three times, and pressurized with H2to 4.0 MPa andheated to 473 K, which was kept constant during the reaction.The reactant and liquid products, after silylation with hexame-thyldisilazane (HDMS) and trimethylchlorosilane (TMSCl) (both≥98.0%, Sinopharm Chemical) in pyridine (AR, Shantou XilongChemical), were analyzed by gas chromatography (Agilent 7890A)using a capillary column HP-1ms (30 m × 0.25 mm × 0.25 m) anda flame ionization detector. The detected liquid products includedethylene glycol, propylene glycol, glycerol, lactic acid, threitol,arabitol, and dehydroxy-pentitols (mainly 1,2,5-pentanetriol and1,2,4,5-pentanetetraol), and dehydrated product hydroxyl furan.Gas products, i.e. CH4and CO2, were also detected in trace amounts,and thus not discussed in this work. Xylitol conversion and productselectivity are reported on a carbon basis, and xylitol reaction activ-ity is reported as molar xylitol conversion rate per mole of metalloaded per hour (h-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | In acetonitrile;Reflux; | To a stirred solution of 9-[(R)-2-[[(S)-[[(S)-l-(isopropoxycarbonyl) ethyl] amino] phenoxy phosphinyl] methoxy] propyl] adenine (lgm, 0.0021 mol) in acetonitrile (20 gms), L-lactic acid (0.17 gms, 0.0019 mol) was added and the reaction mixture was heated to reflux to dissolve the solids. The reaction mass was filtered in hot condition, filtrate cooled to 5°C and maintained for 16 hours. The product was isolated by filtration, rinsed with acetonitrile (6 gms), and dried to obtain 1,0 g of Lactate as a white crystalline powder. HPLC purity: 99.78percent. The XRPD is set forth in Figure 08. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With C11H19AlN2; In dichloromethane; at 20℃; for 24h;Schlenk technique; | The LLA esterification attempts were performed as follows: 1M equivalent of appropriate catalyst in dichloromethane (10mL), LLA (50moleq., 1.02g, 7.06mmol) and MeOH (50 or 200moleq., 0.285 or 1.14mL, 7 or 28mmol) were mixed together and 1mL aliquots were taken after 1, 15, 30min and 24h, the reaction was quenched with addition of one drop of glacial acetic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | With dicyclohexyl-carbodiimide; ethyl cyanoglyoxylate-2-oxime; In tetrahydrofuran; at 63 - 65℃; for 4h; | General procedure: To mixture of compound N-(2-chloro-6-methylphenyl)-2-[6-[4(1-piperazinyl)-2-methyl -4-pyrimidinyl]amino]-5-thiazolecarboxamide (6) (5.1 mol equivalent), the corresponding carboxylic acid (1:1 mol equivalents), DCC (1:1 molequivalents) and oxyma (1:1 mol equivalents) were charged into 4-necked round bottomed flask along with tetrahydrofuran.The slurry was slowly heated at 63-65 C for 4-5 h. Then cooled slowly to room temperature. The reaction mixture was quenched into demineralized water. The obtained solid was collected by vacuum filtration, washed with demineralized water. Suckdried thoroughly to afford crude product. The above obtainedcrude product was dissolved in hot dimethyl sulfoxide (DMSO) (5 volumes to compound weight) and charcoal treatment was given. The hot solution was slowly diluted with water (6 volumes to DMSO quantity) and cooled slowly to room temperature. The solid was colected by vacuum filtration and washed with 10 mL of demineralized water. Drying of the wet compound to get a white coloured product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 48.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; dmap; In tetrahydrofuran; at 80℃; for 24h;Inert atmosphere; | Preparation of (S)-2-((3-((tert-Butoxycarbonyl)amino)propanoyl)oxy)propanoic acid (S)-Lactic acid (755 mg, 8.38 mmol), <strong>[32703-87-0]2,5-dioxopyrrolidin-1-yl 3-((tert-butoxycarbonyl)amino)propanoate</strong> (2.00 g, 6.99 mmol), 4-(dimethylamino)pyridine (85 mg, 0.70 mmol), pyridine (663 mg, 8.38 mmol) and tetrahydrofuran (34 mL) were combined and heated at 80 C. under a nitrogen atmosphere for 24 h. After this time, the solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate (20 ml). The aqueous phase was collected and acidified to pH=3 with 6 N hydrochloric acid, and the mixture was extracted with ethyl acetate (2*20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoic acid (1.67 g, 91%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 5.17 (q, J=6.9 Hz, 1H), 3.45 (m, 2H), 2.60 (m, 2H), 1.54 (d, J=6.9 Hz, 3H), 1.44 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With pyridine; dmap at 60℃; for 48h; Inert atmosphere; | Preparation of (S)-2-(((S)-5-(tert-Butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoic acid Preparation of (S)-2-(((S)-5-(tert-Butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoic acid (S)-Lactic acid (270 mg, 3.00 mmol), (S)-1-tert-butyl 5-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)pentanedioate (1.00 g, 2.50 mmol), 4-(dimethylamino)pyridine (31 mg, 0.250 mmol), and pyridine (237 mg, 3.00 mmol) were combined and heated at 60° C. under a nitrogen atmosphere for 48 h. After this time, the solvent was removed under reduced pressure, and the residue was participated between ethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate (20 ml). The aqueous phase was collected and acidified to pH=3 with 6 N hydrochloric acid, and the mixture was extracted with ethyl acetate (2*20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-(((S)-5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoic acid (726 mg, 77%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.19-5.12 (m, 2H), 2.51-2.42 (m, 2H), 2.18 (m, 1H), 1.91 (m, 1H), 1.54 (d, J=7.2 Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H), CO2H and NH protons not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; dmap; In tetrahydrofuran; at 60℃; for 72h; | Preparation of (S)-tert-Butyl 2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (S)-2,5-dioxopyrrolidin-1-yl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (3.0 g, 11 mmol), (S)-lactic acid (1.0 g, 11 mmol), N,N-dimethylpyridin-4-amine (0.13 g, 0.11 mmol) and pyridine (1.16 mL, 12.5 mmol) were combined in tetrahydrofuran (50 mL) and heated at 60 C. for 72 h. After this time, the reaction mixture was treated with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2*25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoic acid (2.0 g, 99%) as a yellow oil. (S)-2-(2-((S)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoic acid (2.0 g, 8.1 mmol), tert-butyl alcohol (0.90 g, 12 mmol),N,N-dimethylpyridin-4-amine (0.30 g, 2.4 mmol) and dicyclohexylcarbodiimide (2.0 g, 9.7 mmol) were combined and stirred in methylene chloride (60 mL) at ambient temperature for 16 h. After this time, the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-30% ethyl acetate/heptanes) to provide (S)-tert-butyl 2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (0.4 g, 16%) as a colorless oil: 1H NMR (300 MHz, CDCl3) delta 4.99 (dd, J=14.1, 6.9 Hz, 1H), 4.74 (dd, J=6.6, 3.6 Hz, 1H), 3.04 (dd, J=17.4, 3.6 Hz, 1H), 2.84 (dd, J=14.1, 6.6 Hz, 1H), 1.62 (s, 3H), 1.56 (s, 3H), 1.47 (d, J=7.2 Hz, 3H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; dmap; In tetrahydrofuran; at 80℃; for 24h;Inert atmosphere; | Preparation of (S)-2-(((S)-2-((tert-Butoxycarbonyl)amino)-4-methylpentanoyl)oxy)propanoic acid (S)-Lactic acid (658 mg, 7.31 mmol), (S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (2.00 g, 6.09 mmol), 4-(dimethylamino)pyridine (74 mg, 0.61 mmol), pyridine (578 mg, 7.31 mmol), and tetrahydrofuran (35 mL) were combined and heated at 80 C. under a nitrogen atmosphere for 24 h. After this time, the solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate (20 ml). The aqueous phase was collected and acidified to pH=3 with 6 N hydrochloric acid, and the mixture was extracted with ethyl acetate (2*20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-(((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)oxy)propanoic acid (1.83 g, 99%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 5.20-5.14 (m, 1H), 4.88 (m, 1H), 4.32 (m, 1H), 1.81-1.65 (m, 2H), 1.59-1.51 (m, 4H), 1.45 (s, 9H), 0.96 (d, J=6.3 Hz, 6H), CO2H proton not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; dmap; In tetrahydrofuran; at 60℃; for 24h;Inert atmosphere; | Preparation of (S)-2-(((S)-4-(tert-Butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoic acid (S)-Lactic acid (280 mg, 3.11 mmol), <strong>[50715-50-9](S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)succinate</strong> (1.00 g, 2.59 mmol), 4-(dimethylamino)pyridine (32 mg, 0.259 mmol), pyridine (248 mg, 3.11 mmol), and tetrahydrofuran (17 mL) were combined and heated at 60 C. under a nitrogen atmosphere for 24 h. After this time, the solvent was removed under reduced pressure, and the residue was participated between ethyl acetate (30 mL) and 10% aqueous citric acid. The organic layer was separated and washed with water (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-(((S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoic acid (858 mg, 91%) as a colorless oil: 1H NMR (300 MHz, CDCl3) delta 5.51 (m, 1H), 4.58 (m, 1H), 2.96-2.69 (m, 2H), 1.55 (m, 3H), 1.45 (s, 18H), CO2H and NH protons not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; dmap; In tetrahydrofuran; at 80℃; for 24h;Inert atmosphere; | Preparation of (S)-2-(((S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropanoyl)oxy)propanoic acid (S)-Lactic acid (597 mg, 6.62 mmol), (S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (2.00 g, 5.52 mmol), 4-(dimethylamino)pyridine (67 mg, 0.552 mmol), pyridine (437 mg, 5.52 mmol), and tetrahydrofuran (35 mL) were combined and heated at 80 C. under a nitrogen atmosphere for 24 h. After this time, the solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate (20 ml). The aqueous phase was collected and acidified to pH=3 with 6 N hydrochloric acid, and the mixture was extracted with ethyl acetate (2*20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-(((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoyl)oxy)propanoic acid (2.02 g, quantitative) as a colorless semi-solid: 1H NMR (300 MHz, CDCl3) delta 7.34-7.18 (m, 5H), 5.24-5.19 (m, 1H), 4.90 (m, 1H), 4.61 (m, 1H), 3.25 (dd, J=14.1, 8.7 Hz, 1H), 3.07 (m, 1H), 1.55 (d, J=8.7 Hz, 3H), 1.39 (s, 9H), CO2H proton not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.3% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | A solution of 0.1 ml (1.4 mmol) of L-lactic acid was dissolved in 5 ml of DMF, EDCI (0.25 g, 1.54 mmol), H0BT(0.18 g, 1.54 mmol)After stirring and dissolving,A small amount of intermediate 20b, DIEA 0.2 ml was addedAfter dissolving the intermediate 20b slowly0.3 g (0.7 mmol) was added,Room temperature stirring 2h, TLC detection, the end of the reaction, distilled DMF DMF after vacuum and water and methylene chlorideThe organic layer was dried over anhydrous magnesium sulfate and concentrated to a crude product. The crude product was purified by silica gel G column chromatography [eluent (methanol: dichloromethane)= 1: 30 (nu: nu)] to give the compound of Example 35 as a title compound 0. 29 g, yield 85.3% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h; | (0.31 mmol) of intermediate 20 was dissolved in 22 ml of CH2CI2 and 0. 08 g (0.41 mmol) of EDCI, 0. 06 g(0.45 mmol)HOBT,After stirring to dissolve, 0.03 g (0.33 mmol) of L-lactic acid was added, and the mixture was stirred at room temperature for 12 hours and detected by TLC. reaction(Eluent: methanol / dichloromethane / ammonia = 50: 500: 1, V: V: V), and the residue was purified by silica gel column chromatography white Color solid Example 18 A target product, 0.07 g, yield 92.0% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.8% | To a 250 mL round bottom flask was added 16.519 g of D-phenylalanine (0 · lmol, 165 · 19 g / mol)A magnetic stirrer was opened and 0.4 mol of thionyl chloride (118.97 g / mol) was slowly added dropwise with a constant pressure dropping funnel,The reaction was carried out at room temperature for 4 h, and the excess thionyl chloride was removed by rotary evaporation under reduced pressure,To obtain acyl chloride phenylalanine chloride.To a round bottom flask was added 0.3 ml of anhydrous L-lactic acid (90.08 g / mol)Open the magnetic stirrer, ice salt bath reaction 3h,And then reacted at room temperature for 3 h.The low boiling point substance was removed under reduced pressure by means of a rotary evaporator to obtain crude product of phenylalanine lactate hydrochloride.Phenylalanine lactate ester hydrochloride beaker with 40mL of deionized water, was added dropwise with a dropper saturated sodium carbonate solution and shaken until no more precipitate was added to a date, was added 80mL two dichloromethane was shaken extracted 4 times the combined organic phases were extracted 4 times, washed first with a saturated sodium chloride aqueous solution, washed with distilled water until the pH of the wash water to 7.0 to 7.5, dried over anhydrous sodium sulfate 6h, and then using a rotary evaporator distillation under reduced pressure to remove the solvent to obtain a crude product lactate phenylalanine.By molecular distillation phenylalanine lactate The processing conditions are: a molecular distillation conditions: the distillation temperature 85 , the condensing surface temperature 10 , feed flow rate 1.5mL / min, system pressure is 40Pa; two molecular distillation conditions : distillation temperature of 115 , the condensing surface temperature of 15 , feed flow rate 2.0mL / min, pressure at 10Pa.After purification by two molecular distillation, the purity of the lactate phenylalanine reached 96.0% (see FIG. 1 and the structure of FIG. 2), the product yield of 86.8% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; for 16.0h;Reflux; Inert atmosphere; | Compound 14 was prepared following the procedure from Reddy and Reddy (Chem. Pharm. Bull 2010, 58, 953-956): a heterogeneous mixture of 4-bromo-3-chlorobenzene- 1,2-diamine (0.2 g) and (S)-lactic acid in 4N aq. HC1 (2 mL) was refluxed for 16 hours. The reaction mixture was then cooled to room temperature and neutralized with aq. ammonia. The resulting heterogeneous reaction mixture was extracted with EtOAc. The organic layer was dried (Na2S04) and concentrated. The residue was purified by column chromatography (silica gel, 0- 3.5 % MeOH in DCM) to afford the title compound as an orange yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.1% | With water; In propan-1-ol; water; at 60℃; | Add 5-( {3-[2-(3-aminopropoxy)-6-methoxvphenyi] -IH-pyrazoi-5-yi}amino)pyrazine-2-carbonitriie (4.984 g, 1333 rnrnoi, 97.7 wt%) to n-PrOH (15.41 g, 1921 mE) to form a slurry. I-Teat the slurry to 60 c.Add (S)-lactic acid (1.329g. 1475 mmol) to water (19744 mE) and add this solution to the slurry at 58 C. Heat thesolution to 60 C and add n-PrOH (21.07 g, 26.27 mL). Seed the solution with 5-((5-(2-3 -arninopropox )-6-niethox phenx 1)-I I-pv razol-3 -yi)amino)p rajme-2-Larbonltnle 5)- lactate monohydrate (48.8 mg. 0.1 mmol) and cool the solution to 40 C over 35 minutes, Add n-PrOH (60.5 mL) to the slurry at 40 C via a syringe pump over 2 hours andmaintain the temperature at 40 C. Once complete, air cool the slurry to ambienttemperature for 2 hours, the cool the mixture in ice-water for 2 hours. Filter the product, wash the wet cake with 6: 1 (v/v) n-PrOH S HO (15 mE). followed by n-PrOH (15 mE)and dry the wet cake for 20 minutes. Dry the solid overnight at 40 C in vacuo to give the title compound as a white to yellow solid (5621 g, 89.1%), m.p. 157 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1.3 wt% Sn immobilized on high-silica commercial β-zeolite In water at 125℃; for 1.5h; Autoclave; | 2.4. Chemical reaction General procedure: Reaction was performed in an autoclave reactor (Berghof,Germany). About 5 wt% of substrate was added into 10 mL ofwater containing 1 wt% of catalyst. The mixtures were heatedand stirred at several operation conditions. After finished, theproducts were separated and analyzed using a ShimadzuProminence HPLC according to our previous protocols [9]. Inbrief, the liquid product was filtrated using cellulose acetatemembrane filter (0.2 m) prior injected into HPLC. RID-10A(Shimadzu) and Supelcogel C610-H (30 cm 7.8 mm) (Sigma)were used as the detector and the column, respectively. Theoven CTO-20A was operated at 40 °C and H3PO4 (0.05%) wasselected as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In ethanol at 20℃; for 72h; | 2.2 Synthesis of [Cu(κ2-O,O''-lact)2(H2O)2]0.5H2O In a 250mL flask, 5.0mL (59.95mmol) of l-(+)-lactic acid (90% m/m water solution, d=1.20g/mL) were slowly dropped into a suspension of Cu(OH)2 (2.44g, 25mmol) in 100mL of ethanol. The resulting light blue suspension was stirred at room temperature for 3days, monitoring the progress of the reaction with a solubility test in water (diversely from Cu(OH)2, the final product is completely soluble in water). After complete neutralization of Cu(OH)2, the suspension was filtered and the solid was washed with ethanol (50mL) and diethylether (50mL). Yield: 6.09g (85%). IR (Nujol, ν/cm-1): 3472 br (OH), 1652s, 1601s, 1573s. Anal. Calc. for C6H15CuO8.5 requires: C, 25.13; H, 5.27. Found: C, 25.42; H, 5.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; at 70 - 75℃; | General procedure: Stage I (0144) Table 11 illustrates the selected counter ions for the salt screening of beta-GPA. Salt screening experiments were designed in 1:1.1 equivalence (eq) for beta-GPA to counter ion. [table-us-00011-en] TABLE 11 List of selected counterions beta- Counterion Counterion GPA sequence molecular Sample ID (mg) Counterion wt 2162-42-1 to 4 30 Hydrochloric 1 36.46 acid (36-38%)* 2162-42-5 to 8 30 Hydrobromic 2 80.91 acid (48%)* 2162-42-9 to 12 30 Sulfuric acid 3 98.08 (95-98%)* 2162-42-13 to 16 30 Phosphoric acid 4 98.00 (85%)* 2162-42-17 to 20 30 Methane sulfonic 5 96.11 acid (98%)* 2162-42-21 to 24 30 Maleic acid 6 116.07 2162-42-25 to 28 30 Fumaric acid 7 116.07 2162-42-29 to 32 30 Tartaric acid 8 150.09 2162-42-33 to 36 30 Ethanesulfonic 9 110.13 acid 2162-42-37 to 40 30 Ethanedisulfonic 10 190.20 acid 2162-42-41 to 44 30 Citric acid 11 192.12 2162-42-45 to 48 30 Malic acid 12 134.09 2162-42-49 to 52 30 Lactic acid 13 90.08 2162-42-53 to 56 30 Aspartic acid 14 133.1 2162-42-57 to 60 30 Succinic acid 15 118.09 2162-42-61 to 64 30 Sodium 16 40.00 hydroxide 2162-42-65 to 68 30 Potassium 17 56.11 hydroxide 2162-42-69 to 72 30 Oxalic acid 18 90.03 2162-45-1 to 4 30 Magnesium 19 58.32 hydroxide 76 salt screening experiments of beta-GPA with 19 different counter ions were set up with 30 mg of beta-GPA. Sets of four vials for each counterion were set up with four different solvents (0.3 mL): ethanol:water (9:1), isopropanol, acetone:water (9:1) and acetonitrile. (0146) Appropriate amounts of beta-GPA and the counterion were dissolved in the respective solvents and heated to 70-75 C. until dissolved. An additional 0.1 mL of water was added to the samples containing isopropanol, acetone:water (9:1) and acetonitrile. To samples containing L-aspartic acid, around 1.5 mL of water was required to dissolve the solids. After a clear solution was obtained, the samples were left for stirring at room temperature. Solids were observed in the following samples: 2163-42-4, 25, 26, 27, 28, 45 and 53 through 75. The solids were filtered and analyzed by XRPD immediately as wet sample. The samples that did not yield solids were placed in the oven at 50 C. for drying. The following samples resulted in solids after overnight drying: 2162-42-2, 1, 2, 3 and 21 through 24. The experiments with L-aspartic acid, sodium hydroxide, potassium hydroxide, and magnesium hydroxide resulted in the precipitation of either beta-GPA or the counterion. All the experimental observations were recorded after every step and are listed in Table 12. [table-us-00012-en] TABLE 12 Results of Salt screening Sample ID Counterion Solvent After 24 hours After Drying XRPD 2162-42-1 Hydrochloric EtOH:H2O (9:1) Clear Solution White Solid Pattern 1A 2162-42-2 Acid IPA Clear Solution White Solid 2162-42-3 Acetone:H2O (9:1) Clear Solution White Solid 2162-42-4 MeCN White Solid N/A 2162-42-5 Hydrobromic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-6 Acid IPA Clear Solution Gel N/A 2162-42-7 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-8 MeCN Clear Solution Gel N/A 2162-42-9 Sulfuric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-10 IPA Clear Solution Gel N/A 2162-42-11 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-12 MeCN Clear Solution Gel N/A 2162-42-13 Phosphoric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-14 IPA Clear Solution Gel N/A 2162-42-15 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-16 MeCN Clear Solution Gel N/A 2162-42-17 Methanesulfonic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-18 Acid IPA Clear Solution Gel N/A 2162-42-19 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-20 MeCN Clear Solution Gel N/A 2162-42-21 Maleic Acid EtOH:H2O (9:1) Clear Solution White Solid Pattern 6A 2162-42-22 IPA Clear Solution White Solid 2162-42-23 Acetone:H2O (9:1) Clear Solution White Solid 2162-42-24 MeCN Clear Solution White Solid 2162-42-25 Fumaric Acid EtOH:H2O (9:1) White Solid N/A Pattern 7A 2162-42-26 IPA White Solid N/A 2162-42-27 Acetone:H2O (9:1) White Solid N/A 2162-42-28 MeCN White Solid N/A 2162-42-29 L-Tartaric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-30 IPA Clear Solution Gel N/A 2162-42-31 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-32 MeCN Clear Solution Gel N/A 2162-42-33 Ethanesulfonic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-34 Acid IPA Clear Solution Gel N/A 2162-42-35 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-36 MeCN Clear Solution Gel N/A 2162-42-37 Ethanedisulfonic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-38 Acid IPA Clear Solution Gel N/A 2162-42-39 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-40 MeCN Clear Solution Gel N/A 2162-42-41 Citric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-42 IPA Clear Solution Gel N/A 2162-42-43 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-44 MeCN Clear Solution Gel N/A 2162-42-45 L-Malic Acid EtOH:H2O (9:1) White Solid N/A Pattern 12A 2162-42-46 IPA Clear Solution Gel N/A 2162-42-47 Acetone:H2O (9:1) Clear Solution Gel N/... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | Alternative preparation3-(Ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (11. 7 g,60.9 mmol) was added to a solution of (25)-4-[[3-(aminocarbamothioylamino)-2,5-dimethyl-phenyl]methyl]-2-methyl-piperazine-1-carboxylate from Preparation 25 (6.0010 g, 15.2 mmol) and (25)-2-hydroxypropanoic acid (2.20 g, 24.1 mmol) in acetonitrile (15mL) at 0C. The reaction mixture was stirred at room temperature for 48 h. Lithiumhydroxide solution (91.5 ml, 1.0 M) was added to the reaction mixture and stirred for10 min. To the reaction mixture was added water (100 mL) followed by acetic acid (5.23ml, 91.5 mmol). The mixture was reduced to low volume in vacuo. The aqueous residue was neutralised with saturated NaHC03 (aq) and extracted with ethyl acetate (3 x 250mL). The combined organic layers were washed with saturated brine, dried over Mg504 ,filtered and concentrated in vacuo. The obtained residue was purified by silica gel (100-200 mesh) column chromatography eluting with a gradient of 20-100% ethyl acetate inheptanes. Clean fractions were evaporated under reduced pressure to give title20 compound as a colourless non-crystalline solid. (3.05 g, 46.4%) This obtained material(2.58 g, 5.98 mmol) was dissolved in diethyl ether (25.8 ml, 10 ml/g). The mixture wasleft to crystallize over 12 h. The crystals were collected and dried in vacuo to give thetitle material as a crystalline solid. (2.31 g, melting point 120-121 C, 89.5%).1H NMR (600 MHz, DM50-d6) o = 9.34 (s, 1H), 7.38 (d, J = 1. 7 Hz, 1H), 6.85 (d, J =1.7 Hz, 1H), 5.79 (d, J = 5.5 Hz, 1H), 4.69-4.78 (m, 2H), 4.12 (s, 1H), 3.70 (dt, J =13.0, 2. 7 Hz, 1H), 3.33 - 3.43 (m, 2H), 2.90-3.02 (m, 1H), 2. 71 (ddt, J = 11.1, 3.6, 1.9Hz, 1H), 2.60 (dt, J = 11.2, 2.0 Hz, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 2.08 (dd, J = 11.3,3.8 Hz, 1H), 1.90 (td, J = 11.7, 3.5 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H), 1.17 (dd, J = 6.2,30 1.0 Hz, 6H), 1.13 (d, J = 6.7 Hz, 3H). UPLC-M5 Method 5: RT = 1.83 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In ethanol at 20℃; for 72h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.4% | Stage #1: L-Lactic acid In ethanol at 60℃; for 0.25h; Stage #2: bazedoxifene In ethanol at 60℃; for 0.333333h; | 1 0.25 g of L-lactic acid was dissolved in 5 mL of absolute ethanol at room temperature, and heated in a 50 ml reaction flask in a water bath at 60 ° C for 15 min.Adding 1.00 g of bazedoxifene and heating in a 60 ° C water bath for 20 min, after natural cooling,After standing at 5 ° C for 10 h, crystals were precipitated, suction filtered, and dried to give 0.79 g of white crystals.The yield was 66.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | L-(+)-Lactic acid (10 g, 1 1 1 mmol) and (S)-(+)-Nipecotic acid ethyl ester (17.5 g, 1 1 1 mmol) were dissolved in dry DMF (15 mL), and the flask was conditioned with 3 cycles of vacuum/^. Dry DIPEA (14.35 g, 19.3 mL) was added, followed by HATU (50.6 g, 133 mmol) portionwise (exothermic reaction). The reaction was stirred overnight at rt. The reaction mixture was poured into water (500 mL) and extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layer was dried over MgS04, and evapo- rated in vacuo. The crude compound was purified by flash chromatography using a gradient of MeOH in DCM to yield the desired product (S,S)-1 L (12.7 g, 50% as an off-white solid. 1H-NMR (300 MHz, CDCI3) delta 4.59-4.40 (m, 2H), 4.20-4.09 (m, 2H), 3.84-3.62 (m, 2H), 3.15- 2.70 (m, 2H), 2.50-2.40 (m,1 H), 2.21 -2.08 (m, 1 H), 1 .80-1 .51 (m, 3H), 1 .32-1 .25 (m, 6H). GC-MS C11H19NO4 requires: 229, found: 229 (M+), 93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphomolybdic acid In water at 175℃; for 0.0166667h; | 2.3. Catalytic reaction General procedure: Hydrothermal reaction was performed in an autoclave reactor (BR-25, BERGHOF, Germany). In brief, required amounts of the substrate and catalyst were added into 7 mL of water and heated at the designatedtemperatures either in autogenous or aerobic condition. The reactionwas stopped by cooling down the reactor in an ice bath. Theremained cellulose was separated by filtration (ADVANTEC, 0.2 μm)and the filtrate was diluted with water before injected to HPLC. Thesamples were analyzed by using a Shimadzu Prominence HPLCequipped with a RID-10 A as well as a UV detector (210 nm) as describedin our previous study [32]. The yields of the products werecalculated based on carbon weight of the component and cellulose. Inthis context, carbon content of cellulose was determined by using anelemental analyzer (Vario EL cube elemental analyzer). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphomolybdic acid In water at 125℃; for 1h; | 2.3. Catalytic reaction General procedure: Hydrothermal reaction was performed in an autoclave reactor (BR-25, BERGHOF, Germany). In brief, required amounts of the substrate and catalyst were added into 7 mL of water and heated at the designatedtemperatures either in autogenous or aerobic condition. The reactionwas stopped by cooling down the reactor in an ice bath. Theremained cellulose was separated by filtration (ADVANTEC, 0.2 μm)and the filtrate was diluted with water before injected to HPLC. Thesamples were analyzed by using a Shimadzu Prominence HPLCequipped with a RID-10 A as well as a UV detector (210 nm) as describedin our previous study [32]. The yields of the products werecalculated based on carbon weight of the component and cellulose. Inthis context, carbon content of cellulose was determined by using anelemental analyzer (Vario EL cube elemental analyzer). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphomolybdic acid In water at 125℃; for 1h; | 2.3. Catalytic reaction General procedure: Hydrothermal reaction was performed in an autoclave reactor (BR-25, BERGHOF, Germany). In brief, required amounts of the substrate and catalyst were added into 7 mL of water and heated at the designatedtemperatures either in autogenous or aerobic condition. The reactionwas stopped by cooling down the reactor in an ice bath. Theremained cellulose was separated by filtration (ADVANTEC, 0.2 μm)and the filtrate was diluted with water before injected to HPLC. Thesamples were analyzed by using a Shimadzu Prominence HPLCequipped with a RID-10 A as well as a UV detector (210 nm) as describedin our previous study [32]. The yields of the products werecalculated based on carbon weight of the component and cellulose. Inthis context, carbon content of cellulose was determined by using anelemental analyzer (Vario EL cube elemental analyzer). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphomolybdic acid In water at 125℃; for 1h; | 2.3. Catalytic reaction General procedure: Hydrothermal reaction was performed in an autoclave reactor (BR-25, BERGHOF, Germany). In brief, required amounts of the substrate and catalyst were added into 7 mL of water and heated at the designatedtemperatures either in autogenous or aerobic condition. The reactionwas stopped by cooling down the reactor in an ice bath. Theremained cellulose was separated by filtration (ADVANTEC, 0.2 μm)and the filtrate was diluted with water before injected to HPLC. Thesamples were analyzed by using a Shimadzu Prominence HPLCequipped with a RID-10 A as well as a UV detector (210 nm) as describedin our previous study [32]. The yields of the products werecalculated based on carbon weight of the component and cellulose. Inthis context, carbon content of cellulose was determined by using anelemental analyzer (Vario EL cube elemental analyzer). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphomolybdic acid In water at 125℃; for 1h; | 2.3. Catalytic reaction General procedure: Hydrothermal reaction was performed in an autoclave reactor (BR-25, BERGHOF, Germany). In brief, required amounts of the substrate and catalyst were added into 7 mL of water and heated at the designatedtemperatures either in autogenous or aerobic condition. The reactionwas stopped by cooling down the reactor in an ice bath. Theremained cellulose was separated by filtration (ADVANTEC, 0.2 μm)and the filtrate was diluted with water before injected to HPLC. Thesamples were analyzed by using a Shimadzu Prominence HPLCequipped with a RID-10 A as well as a UV detector (210 nm) as describedin our previous study [32]. The yields of the products werecalculated based on carbon weight of the component and cellulose. Inthis context, carbon content of cellulose was determined by using anelemental analyzer (Vario EL cube elemental analyzer). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butanone; at 20℃; for 72h; | A solution of equimolar amounts of baricitinib (40 mg) and A-lactic acid (9.7 mg) in 10 mL methylethylketone (MEK) was prepared. Then the solvent was slowly evaporated in a crystallization dish ( h=30mm d= 50mm) at ambient conditions (T=20C, p= l0l3mbar rH= 30%). After three days, clear colorless needle-shaped crystals grew in the solution. The crystals were separated and dried on filter paper at 40C. Further analysis, in particular the structural determination by single crystal X-ray in example 5, determined that a co-crystal between baricitinib and lactic acid had formed, wherein both molecules were present as neutral species. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.5% | at 10 - 20℃; for 168h; | A mixture of levothyroxine (1000 mg, 1.29 mmol), L-tartaric acid (387 mg, 2.58 mmol), L- lactic acid (928 mg, 10.30 mmol) and isobutyl acetate (10 mL) was stirred with a magnetic stirrer at a speed of 250 rpm. The temperature was thereby kept in the range of from about 10 to 20 C for about 7 days. Thereafter, the solid material was collected by filtration using a suction filter and washed twice with cold isobutyl acetate (~2 x 2.5 mL). The material was then left at room temperature on a filter paper for 0.5 h before it was further dried at room temperature under vacuum (50 mbar) for 12 h to obtain 1303 mg (yield 99.5% of theory) of the levothyroxine L-tartaric acid L-lactic acid co-crystal of the present invention. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; n-heptane at 20℃; for 48h; | 1 General procedure: Base on the solubility test results shown in Table 1, five solvent systems, each a two-solvent mixture, were used in this study. See Table 2 below. Each of twelve chiral organic acids, listed in Table 2, was screened for in-situ precipitation of a (S)-(+)-hydroxychloroquine salt by dissolving the salt-free form of (±)-hydroxychloroquine in each of the five solvent systems to form a solution at a concentration of 40 mg/mL and then adding an equimolar chiral organic acid, in solid form, to 0.5 mL of the solution. The reaction solution was stirred at room temperature for 2 days. |
Tags: 79-33-4 synthesis path| 79-33-4 SDS| 79-33-4 COA| 79-33-4 purity| 79-33-4 application| 79-33-4 NMR| 79-33-4 COA| 79-33-4 structure
A1268116[ 87684-87-5 ]
(S)-2-Hydroxypropanoic-1,2,3-13C3 acid
Reason: Stable Isotope
[ 867-56-1 ]
Sodium (S)-2-hydroxypropanoate
Similarity: 0.94
[ 867-56-1 ]
Sodium (S)-2-hydroxypropanoate
Similarity: 0.94
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H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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